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Journal of Alzheimer’s Disease 34 (2013) 1–114
DOI 10.3233/JAD-121729
IOS Press
Review
Cognitive Enhancers (Nootropics). Part 3:
Drugs Interacting with Targets other than
Receptors or Enzymes. Disease-modifying
Drugs
Wolfgang Froestl∗ , Andrea Pfeifer and Andreas Muhs
AC Immune SA, EPFL, Lausanne, Switzerland
Accepted 7 October 2012
Abstract. Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease,
schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing,
applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and
psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed
in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To
classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in
particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants,
metal chelators, and disease modifying drugs, meaning small molecules, vaccines, and monoclonal antibodies interacting with
amyloid-␤ and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g.,
peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.
Keywords: Amyloid-␤ aggregation inhibitors, antibodies, antioxidants, cognitive enhancers, metal chelators, natural products,
peptides, psychostimulants, tau, vaccines
INTRODUCTION
As of September 30, 2012, there are 26,788 entries
in PubMed under the term cognitive enhancers, 26,781
entries under the term nootropic, and 245 entries under
the term cognition enhancers. Scifinder lists 5,133
references under the research topic nootropic, 541
references under the term cognitive enhancer, and
9,853 references for cognition enhancers. The Thomson Reuters Pharma database lists 1,111 drugs as
∗ Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,
EPFL Quartier de l’innovation building B, CH-1015 Lausanne,
Switzerland. Tel.: +41 21 693 91 21; Fax: +41 21 693 91 20; E-mail:
[email protected]
nootropic agents or cognition enhancers and gives zero
results under the term cognitive enhancer. The term
nootropics was coined by the father of piracetam Corneliu Giurgea in 1972/1973 [1, 2]: NOOS = mind and
TROPEIN = toward.
Nootropics are drugs to treat cognition deficits,
which are most commonly found in patients suffering
from Alzheimer’s disease (AD), schizophrenia, stroke,
attention deficit hyperactivity disorder (ADHD), or
aging. Mark J. Millan and 24 eminent researchers
[3] presented an excellent overview on cognitive
dysfunction in psychiatric disorders in the February
2012 issue of Nature Reviews Drug Discovery and
define cognition as “a suite of interrelated conscious
ISSN 1387-2877/13/$27.50 © 2013 – IOS Press and the authors. All rights reserved
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
(and unconscious) mental activities, including preattentional sensory gating, attention, learning and
memory, problem solving, planning, reasoning and
judgment, understanding, knowing and representing, creativity, intuition and insight, spontaneous
thought, introspection, as well as mental time travel,
self-awareness and meta cognition (thinking and
knowledge about cognition)”.
Since a first review in 1989 on “Families of Cognition Enhancers” by Froestl and Maı̂tre [4], substantial
progress has been made in the understanding of
the mechanism(s) of cognitive enhancers. Therefore,
we propose a new classification to assign cognition
enhancing drugs to 19 categories:
In Part 1, drugs interacting with receptors were
described [5]. In Part 2, drugs interacting with enzymes
were described [1696]. Here, in Part 3, we give an
overview on drugs interacting with targets 3 to 10 and
compounds and preparations of categories 11 to 19.
Disease modifying drugs are aimed to counteract the
progression of a disease. In particular for AD, many
excellent reviews discuss this subject (in chronological order) [6–27]. ␣-secretase activators and ␤- and
␥-secretase inhibitors (and modulators) were presented
in Part 2 of this review. Drugs interacting with amyloid␤ (A␤) and tau including immunotherapy are described
in Part 3.
DRUGS INTERACTING WITH CYTOKINES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Drugs interacting with Receptors (Part 1)
Drugs interacting with Enzymes (Part 2)
Drugs interacting with Cytokines (Part 3)
Drugs interacting with Gene Expression (Part 3)
Drugs interacting with Heat Shock Proteins (Part
3)
Drugs interacting with Hormones (Part 3)
Drugs interacting with Ion Channels (nonReceptors) (Part 3)
Drugs interacting with Nerve Growth Factors
(Part 3)
Drugs interacting with Re-uptake Transporters
(Part 3)
Drugs interacting with Transcription Factors
(Part 3)
Antioxidants (Part 3)
Metal Chelators (Part 3)
Natural Products (Part 3)
Nootropics (“Drugs without mechanism”)
(Part 3)
Peptides (Part 3)
Drugs preventing amyloid-␤ aggregation (Part 3)
16.1. Ligands interacting with amyloid-␤
(Part 3)
16.2. Inhibitors of serum amyloid P component binding (Part 3)
16.3. Vaccines against amyloid-␤ (Part 3)
16.4. Antibodies against amyloid-␤ (Part 3)
Drugs interacting with tau (Part 3)
17.1. Small molecules preventing tau aggregation (Part 3)
17.2. Ligands interacting with tau (Part 3)
17.3. Vaccines against tau (Part 3)
17.4. Antibodies against tau (Part 3)
Stem Cells (Part 3)
Miscellaneous (Part 3)
There is abundant evidence that inflammatory mechanisms within the central nervous system (CNS)
contribute to cognitive impairment via cytokinemediated interactions between neurons and glial cells.
A current hypothesis is that an extracellular insult
to neurons could trigger the production of inflammatory cytokines by astrocytes and microglia [28].
Conversely, A␤ has been shown to induce the expression of interleukin (IL)-1␤, tumor necrosis factor-␣
(TNF-␣) and IL-6 in astrocytes and microglia in culture [29]. One genome-wide analysis in 691 subjects of
mean age of 72.6 years showed that raised chemokine
(C-C motif) receptor 2 (CCR2) expression was the
most strongly associated transcript with lower MiniMental Status Exam scores and accelerated decline in
score over a period of 9 years [30]. Decline in score
over a period of 9 years [30]. The expression profiles of
cytokines in the brains of Alzheimer’s disease patients
were compared to the brains of non-demented patients
[1697]. Also see 11. Antioxidants, Also see 11. Antioxidants, because inflammation is tightly connected with
the oxidative cascade.
TT-301 (MW01-6-189WH; MW-189; Transition
Therapeutics, Toronto following its acquisition of NeuroMedix under license from Northwestern University)
is an inhibitor of microglial cell activation and proinflammatory cytokine production for the potential i.v.
treatment of CNS diseases including AD. Preclinical
characterization of the suppression of brain proinflammatory cytokine upregulation was carried out [31]. A
double-blind, randomized, placebo-controlled Phase I
clinical trial in healthy male subjects (n = 16) started
in the US in May 2011 (Thomson Reuters Pharma,
update of September 14, 2012). The structure was not
communicated.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
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Fig. 1. Drugs interacting with cytokines and with gene expression.
TT-302 (MW01-7-084WH, MW-084; Transition
Therapeutics, Toronto; Fig. 1) is an inhibitor of proinflammatory cytokine production by activated glia for
the potential oral treatment of CNS disorders including
AD, traumatic brain injury and inflammatory diseases
such as arthritis [32]. Phase I clinical trials are expected
for 2012 (Thomson Reuters Pharma, update of September 29, 2012).
Minozac (MW01-2-151SRM, MW-151, Transition
Therapeutics, Toronto following its acquisition of NeuroMedix, under license from Northwestern University)
(Fig. 1) is an inhibitor of pro-inflammatory cytokine
production by activated glia for the potential treatment
of CNS diseases including AD, Parkinson’s disease
(PD), multiple sclerosis, and traumatic brain injury
[33–36] (Thomson Reuters Pharma, update of August
13, 2012).
AD-16 (Guangzhou Institutes of Biomedicine and
Health) is the thiophene analogue of Minozac. It
reduced amyloid-␤ induced spatial learning and memory impairment as potently as donepezil in an
Alzheimer’s mouse model [1698]. (Thomson Reuters
Pharma, update of October 19, 2012).
SEN-1176 (Senexis, Cambridge, UK) (Fig. 1) is a
pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine, which
suppresses A␤42 -induced macrophage production of
nitric oxide, TNF-␣, IL-1␤, and IL-6 in a dosedependent fashion, an activity profile consistent with a
neuroinflammation inhibitor [1711] (Thomson Reuters
Pharma, update of June 24, 2011).
Infliximab (Janssen Biotech, Horsham, PA),
a launched monoclonal antibody against TNF-␣,
improved cognition after intrathecal administration in
a woman with AD [38].
The University of Zurich is investigating an antibody
against the interleukin-12 subunit p40 for the potential treatment of Alzheimer’s disease [1699] (Thomson
Reuters Pharma, update of November 26, 2012).
The development of REN-1189 (formerly CPI1189; Centaur Pharmaceuticals), a TNF-␣ release
inhibitor, was terminated. Also the development of
Semapimod (CNI-1493; Cytokine PharmaSciences,
CPSI, formerly Cytokine Networks), a cytokine
inhibitor, which inhibited A␤ production, plaque formation, and cognitive deterioration in an animal model
of AD was suspended [39, 40].
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DRUGS INTERACTING WITH GENE
EXPRESSION
Gene therapy in AD, a potential for disease modification, was discussed [1715]. An interesting review
on genes and the parsing of cognitive processes was
communicated [42]. Bi-phasic change in brain-derived
neurotropic factor (BDNF) gene expression following antidepressant drug treatment was described [43,
44]. The modulation of Nur77 and Nor-1 expression
by dopaminergic drugs was elucidated [45]. The regulation of GABAA receptor subunit expression by
pharmacological agents was investigated [46]. Gene
therapy in mouse models of Huntington’s disease (HD)
was reviewed [47].
Beperminogene perplasmid (AMG-0001; DS992; Collategene; AnGes MG, formerly MedGene
Bioscience, Osaka, in collaboration with Daiichi
Sankyo) is a hepatocyte growth factor (HGF)
plasmid-based gene therapy for i.m. injection. It
showed nootropic properties with a potential for the
treatment of PD. In November 2011, a Phase III trial
for peripheral arterial disease was expected to be initiated in 2012. In April 2012, the Phase III studies were
still in preparation [48]. A long-term follow-up evaluation of results from the clinical trial TREAT-HGF
was reported [49] (Thomson Reuters Pharma, update
of September 19, 2012).
RVX-208 (Resverlogix, Calgary) (Fig. 1) is an
apolipoprotein A1 (ApoA1) gene expression stimulator for the potential prevention of A␤ plaque
accumulation in AD. In January 2011, data from an
analysis of AD biomarkers in the Phase II ASSERT
trial in 299 patients showed that after 12 weeks
of treatment with 150 mg/day, a positive effect on
A␤40 was seen. A compilation of data on RVX-208
was published in Drugs in R & D [50]. The rationale for the SUSTAIN study (172 patients) and the
ASSURE study (310 patients) was presented [51].
Preclinical evaluations were reported [52, 53] and
clinical data were provided [54–56]. RVX-208 significantly increased high-density lipoprotein (HDL)-C
(p = 0.001), the primary endpoint of the SUSTAIN trial,
a Phase 2b clinical study. SUSTAIN also successfully
met secondary endpoints, showed increases in levels of
Apo-AI (p = 0.002) and large HDL particles (p = 0.02),
both believed to be important factors in enhancing
reverse cholesterol transport activity. In July 2012, the
company was planning to initiate a Phase II trial of
RVX-208 in patients with mild cognitive impairment
(MCI) in the second half of 2013 (Thomson Reuters
Pharma, update of September 27, 2012).
There are several drugs interacting with gene expression in preclinical evaluation (in alphabetical order):
AAV-CYP46A1 (INSERM in collaboration with
sanofi) is an adeno-associated virus (AAV) gene therapy encoding cholesterol 24-hydroxylase (CYP46A1
gene) for the potential injectable treatment of AD.
Reduced A␤ peptides, amyloid deposits, and trimeric
oligomers were observed in APP23 mice. Significant
improvements in cognitive function assessed by the
Morris water maze were seen in Tau22 mice [57]
(Thomson Reuters Pharma, update of June 6, 2012).
See also Part 2, Chapter 2.12. Drugs interacting with
cholesterol 24-hydroxylase (CYP46A1).
AZ-AAV9 (RegenX Biosciences, Washington DC)
is an AAV vector-9 that carries neuroprotective genes
for the potential injectable treatment of AD (Thomson
Reuters Pharma, update of July 27, 2012).
HSD17B10 is a gene, which encodes HSD10, a
mitochondrial multifunctional enzyme that plays a
significant part in the metabolism of neuroactive
steroids and the degradation of isoleucine. Elevated
levels of HSD10 were observed in the hippocampi of
AD patients [58].
PRO-289 (Prosensa Therapeutics, Leiden, the
Netherlands) is the lead from a series of single-stranded
RNA-based antisense oligonucleotide-based therapeutics to inhibit the CTG trinucleotide repeat expansion
of the huntingtin gene (HTT) by preventing the cellular production of aberrantly expanded HTT mRNA and
mutant huntingtin protein (Thomson Reuters Pharma,
update of February 10, 2012).
SynCav (Raft Therapeutics, San Diego CA) is
a gene therapy that upregulates synaptic driven
Caveolin-1 to promote regeneration of neurons for
the potential treatment of neurodegenerative diseases
such as AD, PD, HD, and amyotrophic lateral sclerosis
(ALS) (Thomson Reuters Pharma, update of August
10, 2012).
Intrahippocampal gene transfer of F-spondin, an
activator of the reelin pathway, improved spatial learning/memory in the Morris water maze and increased
the exploration of the novel object in the Novel Object
Recognition test in wild-type mice [59].
lnventiva (Daix, Bourgogne, France) is investigating compounds that increase expression of a target gene
under epigenetic control resulting in increased levels of
a secreted neuronal protein for the potential treatment
of Alzheimer’s disease. (Thomson Reuters Pharma,
update of November 23, 2012). Structures were not
communicated.
Neurologix under license from Keio University was
investigating colivelin, a hybrid peptide composed of
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
activity-dependent neurotrophic factor [60–64] and a
humanin derivative for the potential gene therapy
of AD [65, 66]. The program was terminated. The
development of LX-6171 (Lexicon Pharmaceuticals,
formerly Lexicon Genetics), a small molecule inhibitor
of the SLC6A gene and the LG617 receptor, was discontinued as well.
DRUGS INTERACTING WITH HEAT
SHOCK PROTEINS
Binding of heat shock protein 90 (HsP90) to tau
facilitates a conformational change that results in
its phosphorylation by glycogen synthase kinase 3␤
(GSK-3␤) and its aggregation into filamentous structures [67]. HsP90 regulates tau pathology through
co-chaperone complexes [68].
HsP90 inhibitors, such as PU-H71, PU-3, PU24FCl
(Fig. 2) and PU-DZ8 of the purine class of HsP90
inhibitors from the Memorial Sloan-Kettering Institute
of Cancer Research, New York caused an elimination
of aggregated tau [69–75].
5
PU-H71 is in Phase I clinical trials since July 2011
(n = 40) in the US. The study was expected to be complete by July 2013 (Thomson Reuters Pharma, update
of April 24, 2012).
ALS Biopharma (Doylestown, PA) is investigating
small-molecule brain-penetrant modulators of HsP70
for the potential treatment of neurological disorders
including AD (Thomson Reuters Pharma update of
January 17, 2012).
Conforma Therapeutics (San Diego, CA) presented
a new class of HsP90 inhibitors [76–78] and showed
that E102 (structure not disclosed) promoted selective decrease of the P-tau species in a mouse model
of tauopathy.
KU-32 (University of Kansas, Fig. 2) is a novobiocin derivative acting as an inhibitor of Hsp90 and an
inducer of Hsp70 for the potential treatment of neurological diseases. In transgenic mice expressing human
P301L-mutant tau KU-32 (10 mg/kg for 15 weeks)
reduced cortical levels of CP13-Iabeled tau [1700].
(Thomson Reuters Pharma, update of May 31, 2012).
Lundbeck follows up another series of HsP90
inhibitors (Thomson Reuters Pharma update of March
31, 2011).The structures were not disclosed.
Fig. 2. Heat shock protein 90 inhibitors and a thyrotropin-releasing hormone analogue.
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A␤ accumulation decreased expression of the heat
shock-protein 70-interacting protein (CHIP), which
functions as a tau ubiquitin ligase [79]. CHIP is a
key molecular link between A␤ and tau pathologies. Increasing CHIP levels may have beneficial
effects to decrease tau pathology, because CHIP can
polyubiquitinate tau and may play a crucial role in
preventing accumulation of phospho-tau and neurofibrillary tangles. Heat shock protein 70 prevented both
tau aggregation and the inhibitory effect of preexisting tau aggregates on fast axonal transport [80]. An
exchange of HsP70 for HsP90 is involved in tau degradation [1701].
Excellent reviews on heat shock proteins were previously published [81, 82].
The development of AEG-33773 (Aegera Therapeutics), an allosteric modulator of HsP90 leading to
HsP70 upregulation, was terminated.
DRUGS INTERACTING WITH HORMONES
Sustained efforts went into the exploration of the
cognition enhancing effects of thyrotropin-releasing
hormone and its analogues since it had been recognized as an activator of brain cholinergic systems [83].
Pilot studies of intravenous thyrotropin-releasing hormone in AD were undertaken [84, 85]. Improvement of
cognitive deficits in depressed patients were reported
[86].
Taltirelin (Ceredist, TA-0910; Mitsubishi Tanabe
Pharma) (Fig. 2), an orally active synthetic thyrotropinreleasing hormone analogue, was launched in Japan in
2000 for the treatment of neurodegenerative disease, in
particular spinocerebellar degeneration [87–89]. The
sales in 2011 were USD 226.8 million (Thomson
Reuters Pharma, update of August 30, 2012).
KPS-0373 (Kissei under license from Shionogi)
is a thyrotropin-releasing hormone derivative for the
potential oral treatment of spinocerebellar ataxia in
Phase II clinical trials in Japan (Thomson Reuters
Pharma, update of July 31, 2012). The structure was
not communicated.
Leuprolide acetate implant (VP-4896, Memryte;
Curaxis Pharmaceuticals, Raleigh NC, formerly Voyager Pharmaceutical and DURECT) is a biodegradable
implant formulation of the gonadotropin-releasing
hormone agonist 1-9-luteinizing hormone-releasing
factor-6D-leucine-9-(N-ethyl-L-prolinamide), a nonapeptide, for the treatment of AD in women. A
Phase IIb clinical study plan is currently evaluated. The effects of treatment with leuprolide acetate
depot on working memory in women were described
[90]. Luteinizing hormone modulated the processing of amyloid-␤ protein precursor (A␤PP) and
A␤ deposition [91] and of cognition in transgenic
mice [92]. Several reviews were published [93–96]
(Thomson Reuters Pharma, update of August 24,
2012).
Tesamorelin (Egrifta; TH-9507; Theratechnologies, Quebec and US commercialization partner EMD
Serono and licensee Sanofi) is a stabilized, truncated growth hormone releasing factor (GRF1-44;
ThGRF1-44). In a controlled study of 152 adults (66
with MCI) participants self-administered daily subcutaneous injections of tesamorelin or placebo for 20
weeks, which had favorable effects on cognition in both
adults with MCI and healthy older adults [97] (Thomson Reuters Pharma, update of August 15, 2012).
The development of azetirelin (YM-14673;
Yamanouchi, now Astellas [98, 99]), of calcitriol (Neurocalc; Apollo Biopharmaceuticals,
now MitoKor), of JTP-2942 (Japan Tobacco
[100–102]), of montirelin (CG-3703; CNK-602A;
NS-3; Grünenthal [103]), of orotirelin (CG-3509;
Grünenthal [104–106]), of posatirelin (RGH-2202;
Gedeon Richter [107–109]), of protirelin (DN-1417;
Takeda [110]), of thyrotropin-releasing hormone
analogs (Roche), and of thymoliberin (RX-77368;
Reckitt & Colman [111]) was terminated.
DRUGS INTERACTING WITH ION
CHANNELS (NON-RECEPTORS)
Dysregulation of Ca2+ homeostasis plays a crucial
role in the pathogenesis of AD. In the pathogenesis of AD [1702]. Oligomeric A␤ proteins directly
incorporated into neuronal membranes, formed cationsensitive ion channels (“amyloid channels”) and
caused disruption of calcium homeostasis [112, 113].
A␤ oligomers directly and dose-dependently modulated P/Q-type calcium channels [114]. In triple
transgenic AD mice, upregulated ryanodine receptor
activity led to a reduction of long-term potentiation
[115]. Mutations of presenilin can affect the intracellular calcium levels via the endoplasmic reticulum
calcium stores [116]. The levels of the calcium-sensing
enzyme hippocalcin were elevated in AD brains [117].
Interesting reviews were published [118–121].
Drug repositioning for the treatment of Alzheimer’s
disease was described recently [1703].
ARC-029 (Archer Pharmaceuticals, Roskamp Institute, Sarasota FL) is a blood-brain barrier crossing
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
7
Fig. 3. Two ion channel blocker and three NGF and BDNF stimulators.
formulation of nilvadipine (Fig. 3), a blocker of
L-type voltage-gated calcium channels. The drug has
been approved for a multisite Phase III clinical trial
enrolling more than 500 AD patients in Europe. In
February 2012, the study was expected to begin in the
second half of 2012 (Thomson Reuters Pharma, update
of April 16, 2012).
Nilvadipine (FR-34235; Fujisawa; launched in
Japan in 1989) was extensively characterized in vitro
and in vivo for the potential treatment of AD. It facilitated the clearance of A␤ across the blood-brain barrier
[122, 123]. It prevented the impairment of spatial memory induced by cerebral ischemia combined with A␤
in rats [124, 125]. It also antagonized A␤ vasoactivity [126]. First positive clinical results on nilvadipine
in AD patients were communicated. It was safe and
provided short-term cognitive benefits in AD patients
[127–131].
ARC-031 and ARC-031-SR (Archer Pharmaceuticals; sustained release formulation) is a non-calcium
channel blocking and soluble A␤ reducing nilvadipine
derivative in Phase I clinical trials (Thomson Reuters
Pharma, update of January 3, 2012). The structure was
not communicated.
RNS-60 (Revalesio Corporation, Tacoma WA) acts
on voltage-gated ion channels. It is formulated as
an inhalant anti-inflammatory charge-stabilized nanostructure. The company investigates also the potential
treatment in AD and PD. A Phase I/IIa asthma trial
began in May 2010. In October 2011, data from the
multi-dose stage of the Phase I study were reported.
RNS-60 showed a therapeutic benefit and was safe at
all doses (Thomson Reuters Pharma, update of April
27, 2012). The structure was not communicated.
ZSET-1446 (ST-101, Sonexa Therapeutics, San
Diego CA under license from Zenyaku Kogyo) (Fig. 3)
is in Phase II clinical trials for AD since February 2009.
A second Phase II clinical trial for the treatment of
essential tremor was initiated in the US in May 2011.
It was recognized that ZSET-1446 (ST-101) targeted
T-type voltage-gated calcium channels in mediating
improved cognition in the CNS [132]. In vivo data were
published previously [133, 134] (Thomson Reuters
Pharma, update of July 17, 2012).
AD-N02 (Adamed, Mazowieckie, Poland) is a
sodium channel blocker and dopamine/5-HT stabilizer
for the potential treatment of schizophrenia and bipolar
disorder (Thomson Reuters Pharma, update of August
22, 2012). The structure was not communicated.
Isradipine (Novartis, launched in 1997) is a
L-type voltage-gated calcium channel blocker protecting MC65 neuroblastoma cells from A␤PP
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C-terminal fragment (A␤PP-CTF)-induced neurotoxicity [135–137, 1704].
The development of many drugs interacting with
ion channels was terminated (in alphabetical order):
DMP-543 (Bristol-Myers Squibb; an inhibitor of Mtype K+ channels), enecadin (PAION under license
from Nippon Shinyaku; a sodium and calcium channel
blocker), LB-101, LB-102, LB-217, LB-218, LB-253,
LB-269, LB-301, and LB-302 (Lifelike Biomatic;
modulators of two ionic channels, i.e., ionokines),
linopirdine (DuP 996; Du Pont Merck, Bristol-Myers
Squibb; an inhibitor of M-type K+ channels; despite
promising EEG brain mapping data [138] and an
increase of parietal regional cerebral blood flow in
AD patients [139], the clinical results were disappointing [140]), MEM-1003 (BAY-Z-4406, Memory
Pharmaceuticals under license from Bayer; a L-type
voltage-gated calcium channel [141]), nerispirdine
(HP-184, Hoechst, now sanofi; an inhibitor of Mtype K+ channels), nicardipine (YC-93, Yamanouchi
[142]), nifedipine (BAY-A-1040, Adalat, Bayer
[143]), nimodipine (BAY-E-9736, Nimotop, Bayer
[144–152]), nitrendipine (BAY-E-5009; Bayotensin,
Bayer; all L-type voltage-gated calcium channels
[153, 154]), NP-34 (NP-04634; Noscira, formerly
Neuropharma; a dual calcium channel blocker and
acetylcholinesterase inhibitor [155]), NS-649 (NeuroSearch; a neuron-specific calcium channel blocker
[156]), NSD-761 (NeuroSearch; a selective ion channel modulator); RGH-2716 (TDN-345; a nootropic
neuroselective ion channel blocker; Takeda in collaboration with Gedeon Richter [157–159]), SNX-482
(R-type calcium channel blocker of Neurex, now
Elan Pharmaceuticals [160–162]), SPI-017 (Sucampo;
selective type-2 chloride channel activator), tamolarizine (NC-1100, calcium channel blocker, Nippon
Chemiphar [163–165]), VRX-698 (Valeant Pharmaceuticals International; a potassium channel opener),
and XE-991 (Bristol-Myers Squibb; a KCNQ potassium channel blocker [166, 167]).
DRUGS INTERACTING WITH NERVE
GROWTH FACTORS
The role of neurotrophic factors in AD was discussed [168] as was a neurotrophic rationale for
the therapy of neurodegenerative diseases [169]. The
potential therapeutic use of BDNF, a key regulator
for protein-synthesis dependent long-term potentiation
and long-term memory, in neurological and psychiatric
disorders was presented [170, 171], in particular for
AD [172, 173]. Interestingly, genetic knockdown of
BDNF in triple transgenic AD mice did not alter A␤
or tau pathology [174]. Nerve growth factor (NGF)cholinergic dependency in brain aging, MCI, and AD
was discussed [175–181]. NGF treatment in dementia was described [182]. NGF and AD, new facts
for an old hypotheses were communicated recently
[183]. Hippocampal ProNGF signaling pathways and
amyloid-␤ levels in mild cognitive impairment and
Alzheimer’s disease were elucidated [1705]. It was
claimed that NGF promoted long-term memory formation by activating poly(ADP-ribose) polymerase-1
(PARP-1) [184].
NeuroAid (MLC-601; Danqi Plantan Jiaonang;
Moleac Pte Ltd, Singapore) is a BDNF stimulator
derived from Radix Astragali, Radix Salvia Miltiorrhizae, Radix Paeoniae Rubra, Rhizoma Chuanxiong,
Radix Angelicae Sinensis, Carthamus Tinctorius,
Prunus Persica, Radix Polygalae, Rhizoma Acori
Tatarinowii, Buthus Martensii, Hirudo, Eupolyphaga
Seu Steleophaga, Calculus Bovis Synthetic or Artifactus and Cornu Saigae Tataricae, for the potential
oral prevention of stroke including cerebral infarction
and ischemic stroke and for the potential treatment
of traumatic brain injury in a randomized, doubleblind, placebo-controlled, multicenter, Phase III trial
(n = 1100) since November 2007 in Singapore and the
Philippines. The study was expected to be completed
in 2012 (Thomson Reuters Pharma, update of October
3, 2012).
CERE-110 (AAV2-NGF; NeuroRescue AD; Ceregene, San Diego CA) is an AAV2 vector based gene
delivery system containing cDNA for NGF. A Phase II
clinical trial in mild-to-moderate AD patients (n = 50)
started in May 2009 in the US. The therapeutic potential of CERE-110 was described in detail [185, 186]
(Thomson Reuters Pharma, update of July 20, 2012).
GM-607 (Genervon Biopharmaceuticals, Pasadena
CA) is a motoneuronotrophic factor analogue for the
potential treatment of ischemic stroke, spinal cord
injuries, ALS, AD, HD, and PD. By April 2011, a
Phase II ischemic stroke trial was initiated. By February 2012, further Phase II IND applications were
being prepared for spinal cord injuries, ALS, PD, and
AD (Thomson Reuters Pharma, update of August 28,
2012).
MIM-D3 (Mimetogen Pharmaceutics, Quebec,
Fig. 3) is a small molecule NGF peptidomimetic for
the treatment of AD and dry eye (xerophthalmia). A
Phase II trial for dry eye was initiated in November
2010 [187] (Thomson Reuters Pharma, update of May
17, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
PYM-50028 (Cogane, P58, P63; Phytopharm, UK)
(Fig. 3), a steroidal saponin, stimulated BDNF
release and may be beneficial for the treatment
of PD, AD, glaucoma, and ALS. PYM-50028
reversed neuronal damage induced by 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MTPT) in a mouse
model of PD [188]. In July 2011, FDA granted
PYM-50028 orphan drug status for ALS. In November 2010, recruitment of patients (n = 400) began
in the randomized, double-blind, proof-of-concept,
placebo-controlled, dose-ranging Phase II study
CONFIDENT-PD (Thomson Reuters Pharma, update
of August 16, 2012).
T-817MA (Toyama Chemical, Fujifilm Holding)
(Fig. 3) is a neurotrophic small molecule in Phase
II clinical trials for AD in the US since April 2008.
T-817MA attenuated cognitive impairments in P301L
tau transgenic mice [189], prevented memory deficits
caused by i.c.v. A␤ administration [190, 191], and
attenuated A␤-induced neurotoxicity [192] (Thomson
Reuters Pharma, update of July 30, 2012).
NsG-0202 (ECB-AD, ECT-AD, NsGene A/s, Denmark) is an encapsulated cell biodelivery system to
deliver cells expressing NGF. A Phase Ib trial started
in December 2007 in Sweden. First clinical data were
presented in July 2011. In January 2012, the trial was
expected to be completed in 2012 [193] (Thomson
Reuters Pharma, update of January 17, 2012).
There are several drugs interacting with neurotrophic factors in preclinical evaluation (in alphabetical order):
AL-209 (ADNF-9, SAL; Allon Therapeutics, Vancouver) is an activity-dependent neurotrophic factor
derived nine amino acid sequence peptide and tubulinbinding agent that stimulated PARP-1 for the potential
treatment of CNS and ocular disorders (Thomson
Reuters Pharma, update of March 6, 2012).
AL-309 (Allon Therapeutics, Vancouver) is an
analogue of AL-209 and PARP stimulator for oral,
intranasal and s.c. administration. By October 2012
preclinical development had been completed (Thomson Reuters Pharma, update of October 17, 2012).
AMRS-001 (CNS-001; Amarantus BioSciences,
Sunnyvale CA, formerly CNS Protein Therapeutics
having acquired the relevant IP from Prescient Neuropharma) is a program of therapeutics based on
mesencephalic astrocyte-derived neurotrophic factor
[194], which promoted the survival of dopaminergic
neurons for the potential treatment of PD, AD, and
brain injury. It also protected the heart from ischemic
damage [195] (Thomson Reuters Pharma, update of
October 2, 2012).
9
Catecholamine derivatives (Emory University,
Atlanta, GA) acted like BDNF to activate the tyrosine
kinase B (TrkB) receptor. They have a potential for the
treatment of neurological diseases such as ALS, PD,
and AD (Thomson Reuters Pharma, update of July 27,
2012). Structures were not communicated.
CB-1, CB-2, and CB-3 (Molcode, Tartu, Estonia)
are BDNF mimetics, which activated the TrkB receptor leading to its phosphorylation (Thomson Reuters
Pharma, update of December 27, 2011). The structures
were not communicated.
7,8-Dihydroxy-flavone, a TrkB receptor agonist
and BDNF mimic, reversed memory deficits in a mouse
model of AD [196]. The compound and derivatives
thereof are also evaluated at Emory University in collaboration with the University of Wisconsin [197–199]
(Thomson Reuters Pharma, update of August 10,
2012).
FC29 peptide (University of Queensland, Brisbane,
Australia) is a fragment of the p75 neurotophin receptor that inhibited p75NTR-mediated neuronal death
via regulation of the Trk receptor function for the
potential treatment of AD, PD, and motor neuron disease (Thomson Reuters Pharma, update of May 17,
2012).
Gambogic amine and gambogic amide (Emory
University, Atlanta GA), TrkA receptor agonists with
robust neurotrophic activity, prevented neuronal cell
death [200] (Thomson Reuters Pharma, update of
August 28, 2012).
Gedunin (Emory University, Atlanta GA) and its
derivatives including deoxygedunin are TrkB receptor
agonists for the potential treatment of PD, HD, AD,
HIV-related dementia, ALS, stroke, and multiple sclerosis [201] (Thomson Reuters Pharma, update of April
26, 2012).
JRP-655 (Prous Institute for Biomedical Research,
Barcelona) is a BDNF secretagogue and neuroplasticity modulator (Thomson Reuters Pharma, update of
September 5, 2012). The structure was not communicated.
4-methylcatechol, which increased BDNF content
and stimulated BDNF mRNA expression and synthesis, effectively improved spatial learning and memory
in rats [202, 203].
NeuroAiD II (MLC-901, Moleac Pte Ltd., Singapore), a BDNF stimulator, is a derivative of NeuroAiD
for the potential treatment of global ischemia in
preclinical development (Thomson Reuters Pharma,
update of September 2, 2011).
ND-602 (Neurodyn, Charlottetown, Canada) is a
neuroprotective progranulin (PC cell-growth factor)-
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expressing lentiviral vector for the potential treatment
of PD, AD, and ALS. ND-602 was found to increase
activity of neprilysin and significantly reduced A␤ and
plaque burden in the hippocampus and entorhinal cortex of Tg2576 mice (Thomson Reuters, update of May
25, 2012).
The development of many drugs interacting with
neurotrophic factors was terminated. The most
advanced drug, xaliproden (SR-57746A, Xaprila;
sanofi), a 5-HT1A agonist and stimulator of endogenous neurotrophin synthesis, did not meet the cognition
endpoints in Phase III trials in AD patients, which
applies also to paliroden (SR-57667B; with a biphenyl
instead of the ␤-naphtyl in xaliproden; sanofi, [204]).
The lessons learnt from the xaliproden clinical trials
were discussed [205]. The biological characterization
was reviewed [206].
Also the development of other drugs interacting with neurotrophic factors (in alphabetical
order) was terminated: ABS-200 (American Biogenetic Sciences), ADNF-14 (NIH, activity-dependent
neurotrophic factor-14), AGT-120, and AGT-140
(ArmaGen Technologies); AK-30-NGF (a monoclonal antibody as carrier for the delivery of NGF;
Alkermes), arundic acid (MK-0724, ONO-2506, Arocyte, Ono Pharmaceuticals [207–210]), beta NGF
(tethered to a molecular shuttle; Apollo Life Sciences), CEP-427 (a neurotrophic factor enhancing
small molecule; Cephalon, now Teva), coleneuramide
(MCC-257; Mitsubishi Tanabe Pharma), CX-438
(Cortex Pharmaceuticals), dekafin-1 (a fibroblast
growth factor receptor, agonist and tyrosine kinase
modulator; Enkam Pharmaceuticals); dFGF (dimerized fibroblast growth factor; Massachusetts Institute
of Technology (MIT)/ViaCell Inc.), GDF-1 (Creative
Biomolecules, now Curis; a growth and differentiation factor-1 agonist), glial maturation factor
(Rhone-Poulenc/Regeneron), huIM-13 (a humanized
monoclonal antibody that binds to the TrkA receptor,
Lay Line Genomics), inosine (an NGF, Alseres Pharmaceuticals, formerly Boston Life Sciences (BLSI),
under license from the Children’s Hospital of Boston),
KP-66, KP-447, and KP-546 (Krenitsky), leteprinim
(AIT-082; SPI-205, Neotrofin; Spectrum Pharmaceuticals, formerly NeoTherapeutics), which induced the
expression of NGF, neurotrophin-3, and of basic
fibroblast growth factor [211–216], LM11A-31 (a p75
neurotrophin receptor ligand; Elan), nerve growth
factor agonists (Chiron), neuregulin-2 (cerebellumderived growth factor, NRG2; Acorda Therapeutics
under license from CeNeS and Harvard University), NGF therapy (Lay Line Genomics), NP-901
(Noscira), NS-521 (NeuroSearch), p75 NGF receptor antagonist (Circadian Technologies under license
from the Walter & Eliza Hall Institute), NT-3 (Genentech and StemCells), ReN-1820 (ReNeuron under
license from the University of Bristol), ST-857 (acetylL-carnitine arginine amide; Sigma-Tau [217–219]),
T-588 (Toyama [220–227]), and trofexin (a peptide
neurotrophic factor; Protarga).
DRUGS INTERACTING WITH RE-UPTAKE
TRANSPORTERS (PSYCHOSTIMULANTS)
Psychostimulants exert behavioral-calming and
cognition-enhancing actions in the treatment of ADHD
[228]. Cognition-enhancing doses of psychostimulants
exert regionally restricted actions elevating extracellular catecholamine levels and enhancing neural
signal processing preferentially in the prefrontal cortex. Additional evidence suggests a prominent role of
prefrontal cortex ␣2 and D1 receptors in the behavioral and electrophysiological actions of low-dose
psychostimulants [229, 230]. Excellent reviews on
attention-modulating effects of cognitive enhancers
were published [231–236]. An analysis of student
use (and abuse) of cognitive enhancers was presented
[237]. A review on glycine transporter type 1 (GlyT1)
inhibitors was disclosed [238].
Methylphenidate (Ritalin, Ciba, now Novartis, launched 1956) is a psychostimulant drug,
which increased the levels of dopamine and noradrenaline in the brain through re-uptake inhibition of
the monoamine transporters [239]. Methylphenidate
preferentially increased catecholamine neurotransmission within the prefrontal cortex at low doses
that enhance cognitive functions [240]. Cognitionenhancing doses of methylphenidate preferentially
increased prefrontal cortex neuronal responsiveness
[241]. Methylphenidate decreased the amount of glucose needed by the brain to perform a cognitive task
[242]. The improvement of memory functions by
methylphenidate (and modafinil) in healthy individuals
was described [243].
Most of these experiments were made with
the mixture of erythro and threo stereoisomers.
The active principle of methylphenidate is the
(+)-(␣R,2R)-threo-methylphenidate
hydrochloride
(Dexmethylphenidate, Ritadex; Novartis Pharma
under license from Celgene launched 2002) (Fig. 4),
also available as an extended-release oral formulation
Focalin XR [244]. The spheroidal oral drug absorption system dexmethylphenidate was described [245]
(Thomson Reuters Pharma, update of July 27, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
11
Fig. 4. Psychostimulant cognition enhancers.
Modafinil (Provigil, Lafon Laboratories, later
Cephalon, now Teva, launched 1998) is an inhibitor of
dopamine, noradrenaline, and serotonin re-uptake and
an ␣1 adrenoceptor agonist [246]. Modafinil showed
improvement of cognition and attention in patients
with chronic schizophrenia ADHD [247, 248], in particular in the first episode of psychosis [249, 250]. The
neuronal mechanism by which modafinil affects cognitive and emotional function in schizophrenic patients
was reviewed [251]. Experiments using BOLD functional magnetic resonance imaging (fMRI) in healthy
volunteers showed that modafinil enhanced the efficiency of prefrontal cortical cognitive information
processing, while dampening reactivity to threatening
stimuli in the amygdala, the brain area implicated in
anxiety [252]. Modafinil improved attention in wellrested individuals [243]. Modafinil reliably enhanced
performance on several cognitive tests of planning
12
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
and working memory, but did not improve learning
and delayed recall performance in healthy volunteers
[253]. It may be useful in the treatment of substance
abuse [254]. It improved working memory and sustained attention in cocaine users [255].
The active principle of modafinil is the (R)enantiomer Armodafinil (Nuvigil; CEP-10953;
Cephalon, now Teva launched 2009) (Fig. 4). The
sales of armodafinil in 2011 amounted to USD 266
mil (Thomson Reuters Pharma, update of September
21, 2012).
Atomoxetine (tomoxetine, Strattera, LY-139603;
Lilly; launched 2003) (Fig. 4) is a selective noradrenaline re-uptake inhibitor for the treatment of
ADHD in children and adults [256]. Atomoxetine
inhibited noradrenaline and serotonin transporters with
Ki values of 2.6 and 48 nM, respectively [257]. Atomoxetine improved response inhibition in ADHD
patients and in healthy volunteers via increased activation in the right frontal gyrus measured via fMRI
[258, 259]. Sales in 2011 were USD 620 million
(Thomson Reuters Pharma, update of September 26,
2012).
Lisdexamfetamine (Vyvanse; Shire Pharmaceuticals and New River Pharmaceuticals, launched 2007)
(Fig. 4) is a drug for the treatment of ADHD in
children, adolescents, and adults [260]. Lisdexamfetamine itself is inactive and acts as a prodrug to
dextroamphetamine upon cleavage of the lysine portion of the molecule. Dextroamphetamine inhibited
noradrenaline, serotonin and dopamine transporters
with respective Ki values of 39, 3,830, and 34 nM
[261]. The use of lisdexamfetamine in patients with
dementia was described [231]. Sales in 2011 were
USD 805 million (Thomson Reuters Pharma, update
of September 28, 2012).
Indeloxazine
(YM-08054;
Elen,
Noin,
Yamanouchi, Schering-Plough, now Merck and
Jeil Pharmaceuticals, launched in China and South
Korea) (Fig. 4) blocked the reuptake of noradrenaline
with IC50 of 3.2 ␮M and of serotonin with IC50 of
0.71 ␮M. It is also a MAO inhibitor. It showed learning
and memory improving effects in many animal tests
[262–267].
NS-2359 (NeuroSearch, Fig. 4) is a blocker of
dopamine, noradrenaline, and serotonin re-uptake currently in Phase I clinical trials in Denmark for
the potential treatment of CNS diseases. GSK was
previously developing NS-2359 for the treatment
for depression but discontinued the development
(Thomson Reuters Pharma, update of September 26,
2012).
There are several drugs interacting with re-uptake
transporters in preclinical evaluation (in alphabetical
order):
AM-285 (Cyclocreatine, CincY; Lumos Pharma,
Austin TX based on University of Cincinnati technology) (Fig. 4) is evaluated for the potential treatment
of creatine transporter deficiency, an X-linked autism
spectrum disorder characterized by severe cognitive
impairment [268]. In June 2012, the FDA awarded
cyclocreatine Orphan designation for the treatment
of creatine transporter deficiency (Thomson Reuters
Pharma, update of August 24, 2012).
AS-1522489-00 (Astellas Pharma) is a glycine
transporter-1 inhibitor, a 1,2,4-triazole derivative, of
which only the (S)-atropisomer is biologically active
[269, 270] (Thomson Reuters Pharma, update of January 27, 2012). The structure was not communicated.
Lu-AA42202 (Lundbeck) (Fig. 4) is a triple
dopamine, noradrenaline, and serotonin re-uptake
inhibitor for the potential treatment of major depressive disorders and ADHD (Thomson Reuters Pharma,
update of December 1, 2010).
MLR-1017 (mesocarb, sydnocarb, sidnocarb,
Melior Pharmaceuticals, Exton, PA) (Fig. 4) is
a dopamine transporter inhibitor for the potential
treatment of ADHD and levodopa-induced side effects
in PD. The drug was previously launched in Russia
[271, 272] (Thomson Reuters Pharma, update of April
12, 2012).
PD-2005 (P2D Bioscience, Cincinnati, OH, identical with AHN 2-005, National Institute of Drug Abuse
and US Naval Medical Research Center) (Fig. 4) is an
inhibitor of the dopamine transporter for the potential
treatment of ADHD and for cognitive impairments in
traumatic brain injury. It dose-dependently improved
performance of rats in a delayed-alternation task of
spatial working memory [273] (Thomson Reuters
Pharma, update of June 12, 2012).
RO-4543338 (Roche) is a well-tolerated glycine
transporter inhibitor, which facilitated drug cue extinction [274, 275]. The structure was not communicated.
Selective Serotonin Re-uptake Inhibitors (SSRIs)
showed cognitive enhancing effects [276]. Patients
treated with citalopram showed significant improvements on a cognitive subscale. Paroxetine and fluoxetine improved most of the tested cognitive functions in
a study of 242 depressed patients during one year [277].
Other studies with citalopram, fluoxetine, sertraline,
and zimelidine did not report improvement of memory
and/or reaction time in demented patients [278].
Thiethylperazine (Torecan) (Fig. 4), a drug
approved by the FDA to relieve nausea and vomiting,
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
13
Fig. 5. VMAT2 and DA-reuptake PET ligands.
is an activator of ABCC1 transporters. In a mouse
model of AD expressing the ABCC1 transporter, a
markedly reduced load of A␤ was measured. Deficiency of ABCC1 transporter substantially increased
cerebral A␤ levels [279] (Thomson Reuters Pharma,
update of April 26, 2012).
The development of ASP-2535 (Astellas; a
glycine transporter-1 inhibitor [280]), coluracetam
(BCI-540, MKC-231; BrainCells Inc. under license
from Mitsubishi Tanabe Pharma; an enhancer of
high-affinity choline uptake and K+ -induced release
of acetylcholine [281–288]), CP-101 (CogniPharm,
an i.v. formulation of modafinil), D-serine re-uptake
inhibitors (Memory Pharmaceuticals, now Roche),
flufenoxina (FAES Farma; a dual serotonin and norepinephrine re-uptake inhibitor), glycine transporter-1
inhibitors (Helicon Therapeutics), JNJ-17305600
(NFPS; NPS Allelix; a glycine transporter inhibitor
[289]), PD-2007 (P2D Bioscience, a dopamine transporter inhibitor), SCH-900435 (Org-25935; Organon,
Schering-Plough, now Merck, a glycine transporter-1
inhibitor), SSR-103800 [290–292]) and SSR-504734
(both sanofi; both glycine transporter-1 inhibitors
[293–297]), teniloxazine (sufoxazine, Lucelan,
Metatone, Y-8894, Yoshitomi, Mitsubishi Pharma, a
noradrenaline uptake inhibitor [298],[299–301]), and
tesofensine (NS-2330, NeuroSearch, a monoamine
re-uptake inhibitors of serotonin, dopamine, and noradrenaline [302]) was terminated. The development
of tesofensine for the once-daily oral treatment of
obesity in Phase II trials was also suspended [303].
The vesicular monoamine transporter 2
(VMAT2) located on the membrane of vesicles
is responsible for storing and packaging neurotransmitters into monoamine vesicles or granules.
Imaging VMAT2 in the brain provides a measurement
reflecting the integrity of dopaminergic, noradrenergic
and serotonergic neurons [304]. Positron emission
tomography (PET) ligands for the VMAT2 have
become valuable diagnostic tools.
(+)-[11 C]-dihydrotetrabenazine (DTBZ) (Fig. 5)
allows the determination of the striatal monoaminergic
presynaptic terminal density. In a study enrolling 20
patients with dementia with Lewy bodies (DLB), 25
AD patients, 7 patients with frontotemporal dementia,
and 19 elderly controls clinicians could accurately
differentiate between the different forms of dementia
[305–307]. The uptake of (+)-11 C-DTBZ in the stria-
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
tum of AD patients mainly reflecting the presynaptic
dopaminergic system was unchanged compared to
controls. The striatal uptake in DLB and PD patients
was significantly decreased [308].
18 F-Florbenazine (18 F-AV-133; 18 F-FP-DTBZ;
Avid Radiopharmaceuticals, Philadelphia PA, a subsidiary of Lilly, under license from University of
Michigan) (Fig. 5) is in Phase III clinical evaluation.
In May 2012, an open-label, single-blind, Phase II/III
study (NCT01550484; 18 F-AV-133-B04) was initiated in patients with undiagnosed movement disorders
(n = 150) in the US to assess the safety and efficacy
of florbenazine in differentiating PD. At that time, the
study was scheduled to complete in September 2014.
For the synthesis, see [309]; for the binding characteristics in rat striatum and hypothalamus homogenates
(Kd = 0.19 and 0.25 nM, respectively), see [310, 311].
The whole body biodistribution was studied [312].
18 F-AV-133 was used for noninvasive assessment of
the vesicular monoamine transporter type 2 in 17 PD
patients and 6 healthy controls. VMAT2 binding potential was decreased by 81% in the posterior putamen,
70% in the anterior putamen, and 48% in the caudate
nucleus of PD patients [313].
This ligand is a valid measure of dopaminergic
neuron integrity. The in vivo assessment in patients
with DLB and AD was reported [314]. The optimal
scanning time window was elucidated [315]. For PET
imaging in a MPTP-induced mouse model of PD, see
[316] (Thomson Reuters Pharma, update of August 7,
2012).
11 C-␤-CFT and 18 F-␤-CFT (Fig. 5) proved to
be valuable PET ligands due to their high affinity
interaction with dopamine re-uptake sites. AD patients
showed a reduction of 11 C-␤-CFT in putamen and caudate of about 20%. Thus the putamen and the caudate
nucleus were equally affected in contrast to PD, which
showed predominantly putaminal reduction [317]. In
PD, the mean uptake of 18 F-␤-CFT in the contralateral putamen was reduced to 31% and in the ipsilatral
putamen to 45%. In the caudate nucleus, the uptake
was reduced contralaterally to 67% and ipsilaterally to
77% [318]. For an exhaustive review, see [319].
123 I-Ioflupane (123 I-FP-CIT; Amersham, now GE
Healthcare) (Fig. 5) is a SPECT ligand launched in
2000. It is the ligand of choice to differentiate between
AD and DLB patients [320, 321]. It is valuable for
the diagnosis of Parkinsonian syndromes [322]. SERT
dependent 123 I-ioflupane uptake allows a more comprehensive assessment of neurochemical disturbances
in degenerative Parkinsonism [323–325] (Thomson
Reuters Pharma, update of August 14, 2012).
DRUGS INTERACTING WITH
TRANSCRIPTION FACTORS
cAMP response element-binding (CREB) protein
and the discovery of cognitive enhancers was reviewed
[326–328]. CREB phosphorylation as a mechanistic marker in the development of memory enhancing
AD therapeutics was described [329]. The current
knowledge of key calcium signal-regulated transcription factors, namely CREB, nuclear factor of activated
T-cells, and downstream regulatory element antagonist modulator (DREAM) and memory formation was
summarized [330]. A␤ disrupted activity-dependent
gene transcription required for memory through the
CREB-regulated transcription co-activators CRTC1
[331]. The GABAB receptor antagonist SGS742
improved spatial memory and reduced protein binding to CREB2 in the hippocampus [332] (see Part
1, Chapter 1.10.2 GABAB receptors). CREB antisense oligonucleotide administration into the dorsal
hippocampal CA3 region impaired long- but not shortterm spatial memory in mice [333].
The lack of DREAM protein enhanced learning and
memory and slowed brain aging [334].
SRF/MYOCD inhibitors (Socratech LLC,
Rochester NY) are small molecule inhibitors against
serum response factor and myocardin, which are
interactive transcription factors in vascular smooth
muscle cells for the potential treatment of AD
[335]. For a review on the imbalance of vascular
molecules in AD, see [336] (Thomson Reuters
Pharma, update of February 15, 2012). Structures
were not communicated.
The development of CREB modulators (Helicon
Therapeutics) and of EPAC inhibitors (exchange protein directly activated by cAMP, a guanine nucleotideexchange factor; Scottish Biomedical [337]) was
terminated.
ANTIOXIDANTS
Soluble A␤ oligomers localize to mitochondria
and interfere with their normal functioning causing an overproduction of reactive oxygen species
(ROS), inhibiting respiration and ATP production and
damaging the structure of mitochondria [338–340].
Some authors, however, claim that the early impairments of mitochondrial dysfunction and oxidative
stress may precede A␤ overproduction and deposition [341–343]. Excellent reviews were presented
over years [344–347]. Possibilities of intervention of
antioxidant pathways in AD were discussed [348, 349].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
15
Fig. 6. Mitochondria-targeting antioxidants.
Also see Chapter 3. Cytokines, as inflammation is
tightly connected with the oxidative cascade.
Over the years, clinicians have explored treatment
of AD patients with antioxidants. Free radicals can
be scavenged by dietary means. Compounds such as
acetyl-L-carnitine, curcumin [350], Gingko biloba
extracts such as EGb 716, (R)-α-lipoic acid, melatonin, morin, trolox, vitamin C [351], and vitamin E
[352–355] were tested in clinical trials in AD patients.
The results were disappointing [356–372]. As a consequence of a landmark study, clinicians even advise AD
patients not to take large doses of vitamin E or ␣-lipoic
acid [373].
Many clinical trials were also carried out with
synthetic antioxidants such as edaravone (MCI-186,
Mitsubishi [374],[375–377]), idebenone (CV-2619,
Avan, Catena, Noben, Sovrima; Takeda [378–380]),
and the derivatives of 21-aminosteroids (Upjohn’s
lazaroids, such as tirilazad or U-74006F, U-74389G,
U-74500A, U-75412E, U-78518F, and U-83836E
[381–384]). None of these compounds produced statistically significant therapeutic benefits for AD patients.
MitoQ (redox mixture of mitoquinone and mitoquinol; Antipodean Pharmaceuticals, Menlo Park
CA, under license from the University of Otago;
Fig. 6 shows the oxidized form) is a brain penetrating mitochondria-targeting antioxidant [385–388]. It
selectively blocked mitochondrial oxidative damage
and prevented cell death [389–394]. It is evaluated in
Phase II clinical trials for the treatment of PD and liver
damage. Clinical trials for the treatment of Friedreich’s
ataxia and sunburn were abandoned (Thomson Reuters
Pharma, update of June 18, 2012).
A potential follow-up compound is MitoVitE
(Fig. 6) [395, 396]. The development of MitoPBN
(Antipodean Pharmaceuticals, Menlo Park CA)
(Fig. 6) consisting of the spin trapping agent ␣phenyl-N-tert.-butyl-nitrone [397, 398] conjugated to
triphenyl-phosphonium bromide was terminated [399]
(Thomson Reuters Pharma, update of June 18, 2012).
MTP-131 (Bendavia, SS-31, Szeto-Schiller peptide; Stealth Peptides Inc., Newton Centre MA) (Fig. 7)
is a cell-permeable mitochondria-targeting antioxidant
tetrapeptide (NH2 -D-Arg-Dmt-Lys-Phe-NH2 ), which
is in Phase II clinical trials for ischemia reperfusion
injury since September. 2010 (EMBRACE–STEMI
trial). It will further be investigated for the treatment
of eye, neurological, mitochondrial, and metabolic
16
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Fig. 7. The Szeto-Schiller peptide, a manganoporphyrin antioxidant and CNB-001.
diseases [400–402],[403] (Thomson Reuters Pharma,
update of June 15, 2012).
VP-20629 (OX1; IN-OX1; OX1; OXIGON, Indole3-propionic acid; ViroPharma, Exton PA, under license
from Intellect Neurosciences, New York University
and Mindset BioPharmaceuticals) is an antioxidant and
A␤ aggregation/deposition inhibitor. The prevention of
A␤ induced neurotoxicity by indole-3-propionic acid
was described [404]. The rationale behind the selection
of OXIGON as a potential disease-modifying therapy
for Alzheimer’s disease was presented [1706]. Preliminary data from a multiple-dose Phase Ib trial for
AD were reported in October 2010. It appears that
ViroPharma wants to pursue the drug for the indication
Friedreich’s ataxia only (Thomson Reuters Pharma,
update of August 17, 2012).
There are several antioxidants in preclinical evaluation (in alphabetical order):
Catalytic manganoporphyrine antioxidants, such
as AEOL-10113, AEOL-10150, AEOL-10201 and
AEOL-11207 (Aeolus Pharmaceuticals, Mission
Viejo CA; Fig. 7) may be promising for the treatment of
PD and ALS [405–407] and ischemic stroke [408–412]
(Thomson Reuters Pharma, update of April 23, 2012).
CNB-001 (The Salk Institute for Biological Studies)
(Fig. 7) is a curcumin derivative for potential treatment
of traumatic brain injury and stroke (Thomson Reuters
Pharma, update of November 9, 2011).
DL-3-n-butylphtalide (NBP, Hebei, China) is a natural antioxidant extracted from seeds of Apium and
a powerful free radical scavenger [413]. It protected
dopamine neurons in a rotenone model for PD [414].
FRP-0924 (gemifloxacin, Neuron BioPharma,
Granada, Spain) is an antioxidant and neuroprotectant
for the potential treatment of neurodegenerative diseases including AD. FRP-924 crossed the blood-brain
barrier and prevented neuronal death. As fluoroquinolones are generally well tolerated with most side
effects being mild and serious adverse effects being
rare, it is expected that the drug will enter Phase II
rapidly (Thomson Reuters Pharma, update of August
14, 2012).
IAC (Cerebricon, Finland and Medestea Research,
Torino, Italy) (Fig. 8) is a novel radical scavenger react-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
17
Fig. 8. Antioxidants in preclinical evaluation.
ing with most carbon-, nitrogen-, and oxygen-centered
radicals of biological interest [415–418]. Daily treatment with IAC (3–30 mg/kg i.p.) decreased mortality,
enhanced cognitive functions in the water maze, and
reduced the A␤ plaque burden in hA␤PP transgenic
mice [419].
Lipid soluble antioxidants (OXIS International,
Beverley Hills CA) mimic the activity of the body’s
natural cell membrane-protecting antioxidant vitamin
E for the potential treatment of cardiovascular diseases,
diabetes, AD, and PD (Thomson Reuters Pharma,
update of June 12, 2012). The structures were not
communicated.
Lipocrine and Memoquin, dual acetylcholinesterase inhibitors and antioxidants (University of
Bologna), were described in Part 2, Chapter 2.1.1.3.
(formulae in Part 2 in Fig. 6).
NPS-0155 (Neuron BioPharma, Granada, Spain) is
an antioxidant and neuroprotective compound for the
potential treatment of AD and other neurodegenerative
diseases (Thomson Reuters Pharma, update of April
27, 2012). The structure was not communicated.
PAN-811 (3-AP; NSC-663249; OCX-191; Triapine,
Panacea Pharmaceuticals, Gaithersburg MD) (Fig. 8) is
a ribonucleotide reductase inhibitor, calcium ion chelator, and radical scavenger for the potential treatment
of AD and ischemia [420, 421] (Thomson Reuters
Pharma, update of February 25, 2011).
S-52 (Shanghai Institute of Materia Medica) (Fig. 8)
is a sinomenine derivative, an active natural product
from the Chinese herb Sinomenum acutum. It is a scavenger of free radicals. It attenuated the toxicity of A␤
to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain
[422].
There are numerous preclinical reports of drugs
and natural products, which, in addition to their radical scavenging properties, also prevented A␤-induced
neurotoxicity, such as peoniflorin [423], 2,2 -pyridoin
[424], quetiapine [425]), stemazole (Fig. 8) [426], and
zeatin (Fig. 8) [427].
Dual free radical scavengers and A␤ binding ligands were described [428, 429].
The development of many antioxidants was terminated (in alphabetical order) of AN-808 (Athena
Neurosciences, now Elan Pharmaceuticals), AO-2 and
AO-3 antioxidants (Antoxis), CNSB-002 (AM-36;
Relevare; AMRAD, formerly Zenyth Therapeutics
[430] [431, 432]), CPI-1189 (Centaur [433, 434]), disufenton sodium (Cerovive, NXY-059, AstraZeneca,
which was in Phase III clinical trials for the treatment
of acute ischemic stroke [435–445]), FR-210575 (Fujisawa [446]), MDL-101002 (Hoechst Marion Roussel,
now sanofi [447, 448]), and raxofelast (IRFI-016,
Biomedica Foscama Industria [449–452]).
METAL CHELATORS
The metallobiology of AD was investigated in great
detail over the last fifteen years. Excellent reviews were
18
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
published (in chronological order) 2001: [453], 2002:
[454], 2003: [455], 2006: [456], 2007: [457–459],
2008: [460–462], 2009: [463–467], 2010: [468–472],
2011: [473–478], 2012: [479–485], 2012: [1707].
DP-b99 (D-Pharm, Rehovot, Israel) (Fig. 9) is an
i.v. prodrug of the calcium and zinc chelator BAPTA
for the potential treatment of stroke and traumatic
brain injury. It is in Phase III clinical trials for stroke
since October 2009. First reports on clinical results
were communicated [486–488]. Also preclincial data
were disclosed [489–491] (Thomson Reuters Pharma,
update of February 3, 2012).
PBT-2 (Prana Biotechnology, Parkville, Australia)
(Fig. 9) is an oral zinc ionophore metal-protein attenuating compound that reduced levels of soluble A␤ and
tau hyperphosphorylation [492]. A Phase IIa study in
AD patients (n = 78), started in December 2006 with
daily doses of 50 or 250 mg or placebo over three
months, was completed in January 2008. A significant reduction of A␤42 levels in the cerebrospinal fluid
(CSF) was seen in the 250 mg group. This dose also
significantly improved executive function performance
in the category fluency and the trail making cognitive tests compared to placebo [493, 494]. In January
2012, the FDA approved an IND to initiate a randomized, multicenter, double-blind, placebo-controlled,
parallel-group, safety, tolerability, and efficacy Phase
IIa trial in early- to mid-stage HD patients (n = 100) in
the US and Australia. In April 2012, the first patient
was dosed in this trial. By June 2012 the trial had
been initiated in Australia. Data are expected in the
second half of 2013. The compound was extensively
characterized in preclinical studies [495–497] (Thomson Reuters Pharma, update of October 2, 2012). See
also Chapter 17.1. Small molecules preventing tau
aggregation.
AEN-100 (Synthetic Biologics, formerly Adeona
Pharmaceuticals, Ann Arbor, MI) is a once-daily, gastroretentive, sustained-release, oral tablet formulation
of zinc acetate for the potential treatment of ALS and
AD. By November 2011, a Phase I study for ALS
patients was underway (Thomson Reuters Pharma,
update of September 19, 2012).
Other metal chelators are currently in preclinical
evaluation (in alphabetical order):
Aom-0937 (Hangzhou Adamerck Pharmlabs,
China) is a prodrug of DP-b99 (Thomson Reuters
Pharma, update of July 28, 2011). The structure was
not communicated.
DP-460 (D-Pharm, Rehovot Israel) (Fig. 9) is a
membrane active chelator derivative of the calciumspecific chelator BAPTA that modulates copper and
zinc homeostasis to inhibit oxygen radicals and plaque
formation. It is in preclinical evaluation for the potential oral treatment of AD and ALS (Thomson Reuters
Pharma, update of November 1, 2011). It appears that
DP-460 was preferred to DP-109 [498]. Both compounds have been evaluated as neuroprotectants in
a transgenic mouse model of ALS [499] (Thomson
Reuters Pharma, update of August 7, 2012).
Deferoxamine (SAN-121; Sanomune, a subsidiary
of DiaMedica under license from HealthPartners
Research Foundation, Winnipeg, Canada) (Fig. 10) is a
nasally-delivered iron chelator improving performance
in a radial arm water maze in P3301L tau transgenic mice [500] (Thomson Reuters Pharma, update
of December 23, 2011).
HLA20A (Technion Haifa) (Fig. 10) is a combination of an 8-hydroxy-quinoline metal chelator,
which was carbamoylated at the 8-hydroxy function
to interact with acetylcholinesterase as in rivastigmine
[501, 502]. See Part 2, Chapter 2.1.1.10. Dual acetylcholinesterase inhibitors and metal chelators.
PA-1637 (Palumed, France) is an A␤ plaque
production-inhibiting copper chelating agent (Thomson Reuters Pharma, update of May 28, 2012). The
structure was not communicated.
PBT-3 and PBT-4 (Prana Biotechnology, Parkville,
Australia) are non-8-hydroxyquinoline metal protein attenuating compounds, potential follow-ups of
PBT-2. (For both Thomson Reuters Pharma, update
of November 2, 2011). The structures were not
communicated.
Triazole-pyridine derivatives as inhibitors of
metal-induced A␤ aggregation were described [503].
VAR-10200 (HLA-20; Varinel, West Chester, PA)
(Fig. 10) is a dual iron-chelating agent and MAO-B
inhibitor for the potential treatment of age-related macular degeneration [501] (Thomson Reuters Pharma,
update of February 24, 2012). See Part 2, Chapter 2.26.
Drugs interacting with Monoamine Oxidase.
VAR-10300 (M-30; Varinel, West Chester, PA,
Technion and the Weizmann Institute) (Fig. 10)
combines the iron-chelating properties of 8-hydroxyquinoline with the MAO inhibitor moiety of rasaglinine
[504–517] (Thomson Reuters Pharma, update of
September 24, 2012). See also Part 2, Chapter 2.26.
Drugs interacting with Monoamine Oxidase.
The development of many metal chelators was
terminated (in alphabetical order): desferrioxamine [518–520], Gero-46 (clioquinol, Gerolymatos);
NG-1 and PBT-1 (clioquinol, Prana Biotechnology [521, 522]); phanquinone (PN Gerolymatos);
tetrathiomolybdate (a copper chelating agent of
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
19
Fig. 9. Metal chelators.
Fig. 10. Metal chelators II.
Adeona Pharmaceuticals, formerly Pipex under license
from the University of Michigan); the iron chelator
VAR-10100 (VK-28) [523–526] and VK-11 and VK12 (Prana Biotechnology).
NATURAL PRODUCTS
Excellent reviews on naturally occurring phytochemicals for the prevention and treatment of AD have
20
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
been presented [527–532]. An overview on “natural
substances and AD: from preclinical studies to evidence based medicine” was published recently [533].
Mentat (BR-16A; Himalaya Drug Co.) is a standardized mixture of herbal extracts, which has been
launched in India and the US (as MindCare) in
November 2000 for the treatment of cognitive deficits
(Thomson Reuters Pharma, update of November 6,
2000).
YY-280 (Yucrid; Yuyu, South Korea) is a combination therapy of ticlopidine and EGb-761 (tanamin,
a Ginkgo biloba extract) administered as a tablet
for the treatment of apoplexy and myocardial infarction. The drug was registered in Korea in May 2008
[534] (Thomson Reuters Pharma, update of April 11,
2012).
SK-PC-B70M (SK Chemicals Life Science, South
Korea) is derived from the dried root of Pulsatella
koreana (baekduong). A randomized, double-blind,
placebo-controlled Phase III clinical trial for the treatment of mild-to-moderate AD patients (n = 256) was
initiated in November 2010 in South Korea. SK-PCB70M improved scopolamine-induced impairments of
memory consolidation in rats [535, 536]. It had antioxidant activity and reduced A␤ levels in the brains of
Tg2576 mice [537, 538]. It alleviated the neurologic
symptoms in G93A-SOD1 ALS mice [538] (Thomson
Reuters Pharma, update of February 28, 2012).
Circadin (KI-1001, NSC-56423; Neurim Pharmaceuticals, Tel Aviv) is an oral controlled-release
formulation of melatonin (i.e., melatonin acetamide)
and was launched in 2007 for the treatment of primary
insomnia. A Phase II clinical trial was initiated in Israel
in patients with MCI (n = 50) in October 2007. Another
Phase II clinical trial was initiated in the US, UK, and
Israel in patients with mild-to-moderate AD (n = 140)
treated with an acetylcholinesterase inhibitor to evaluate the effects of add-on Circadin (2 mg) on decline in
cognitive skills, global functioning, and daytime somnolence in September 2009 (Thomson Reuters Pharma,
update of September 26, 2012).
KD-501 (Kwang Dong Pharmaceutical Co., Seoul)
is an extract from the Scrophulariae radix. The drug is
in Phase II clinical trials for AD since March 2009
(Thomson Reuters Pharma, update of February 11,
2011).
PPLs (NatureWise Biotech, Taipeh, Taiwan) are
prenylflavanone compounds extracted from Taiwanese
propolis in Phase II clinical trials. A pilot AD program
of PPLs in combination with Aricept was initiated in
November 2010 (Thomson Reuters Pharma, update of
July 10, 2012).
PTX-200 (Phytrix, Munich, Germany) is a plantderived neuroprotectant for the potential treatment of
PD. A Phase I/IIa clinical evaluation in the UK was
successfully completed (Thomson Reuters Pharma,
update of February 1, 2012).
Resveratrol is a natural phyto compound, which
activated Sirtuin-1 [539–544]. It reduced A␤ accumulation [545–548]. It remodeled soluble oligomers
and fibrils of A␤ into off-pathway conformers [549].
Resveratrol is not a direct activator of SIRT1 enzyme
activity [550]. Resveratrol improved memory deficits
in mice fed a high-fat diet [551]. Subchronic oral
toxicity and cardiovascular safety pharmacology studies were carried out [552]. The biosynthesis of
resveratrol in yeast and in mammalian cells was
achieved [553]. The Georgetown University Medical
Center in Washington DC started at Phase II, randomized, double-blind, placebo-controlled study in
patients with mild-to-moderate AD (n = 120) in the US
in May 2012 (NCT01504854). A novel application in
HD was discussed recently [554]. See also in Part 2,
Chapter 2.40, Drugs interacting with Sirtuin, formula
in Part 2, Fig. 23 (Thomson Reuters Pharma, update of
June 22, 2012).
RPh-201 (Regenera Pharma, Rehovot, Israel) is a
subcutaneous formulation of an agent derived from
a traditional medicinal plant. A Phase I/IIa randomized, double-blind, placebo-controlled trial in healthy
volunteers and adults with AD (n = 56) started in January 2012 in Canada. A topical formulation is currently
evaluated in a Phase II study in patients with chronic
ulcerated wounds (n = 15) in Israel (both Thomson
Reuters Pharma, update of January 31, 2012).
VR-040 (apomorphine as dry powder inhaled
formulation, Vectura, Chippenham, UK) is being
developed in Phase II clinical trials for the potential
treatment of PD since June 2006 (Thomson Reuters
Pharma, update of October 3, 2012).
Exebryl-1 (ProteoTech, Kirkland, WA and Chinese
licensee Tasly Pharmaceuticals) is a synthetic compound with molecular weight of about 300 Da, one of
the components of an Amazonian vine Uncaria tomentosa extract, which reduced aggregation of both A␤
and tau. A Phase I clinical trial for AD was initiated in
July 2008 (Thomson Reuters Pharma, update of June
8, 2012).
Taisi (Beijing SL Pharmaceutical under license from
Xuanwu Hospital of Capital Medical University), a
capsule formulation of a stilbene analogue isolated
from an unspecified organism, is in clinical studies in
China since February 2011 (Thomson Reuters Pharma,
update of June 29, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
There are many natural products in preclinical evaluation as potential drugs for the treatment of AD (in
alphabetical order):
Alpha-mangostin, a polyphenolic xanthone derivative from mangosteen, concentration-dependently
attenuated neurotoxicity induced by A␤1-40 or A␤1-42
oligomers (EC50 = 3.89 nM and 4.14 nM, respectively)
[555].
Anatabine (Star Scientific, Glen Allen VI through
its subsidiary Rock Creek Pharmaceuticals in collaboration with the Roskamp Institute) reduced A␤
when applied to cells [556] (Thomson Reuters Pharma,
update of January 3, 2012).
Andrographis paniculata leaves extract showed
cerebroprotective and nootropic activities in rats [557].
Apomorphine is an inhibitor of A␤ fibril formation
[558]. Apomorphine treatment of AD mice promoted
A␤ degradation [559]. Roles of apomorphine for regulated ␣-cleavage, autophagy, and antioxidation were
discussed [560].
AX-00111 (Axonal Consultoria Tecnologica Ltda,
Sao Paulo Brazil) is a plant-derived compound for the
potential treatment of AD (Thomson Reuters Pharma,
update of June 1, 2012).
Axona (Accera Inc., Broomfield, CO) is a new
medical food therapy for AD patients [561, 562].
It contains the proprietary formulation of mediumchain triglycerides, mostly caprylic triglyceride. The
rationale for the use of Axona is based on the finding that the cerebral hypometabolism (i.e., impaired
glucose metabolism) is an early sign of AD. Mediumchain triglycerides are metabolized in the liver
resulting in the production of the ketone body betahydroxybutyrate, which is transported to the brain
to provide an alternative fuel source for cerebral
metabolism [563, 564]. See also [565].
Bacopa monnieri has shown memory free recall
enhancing effects in adult humans [566]. Neuroprotective effects in experimental models of dementia were
described [567].
Baicalein (5,6,7-trihydroxyflavone) protected cortical neurons from A␤25-35 -induced toxicity [568] and
in a one dose pre-treatment at 5 and 10 mg/kg i.p.
attenuated A␤25-35 -induced amnesia in mice in a stepthrough passive avoidance paradigm. Post-treatment
for 7 or 13 days (10–15 mg/kg i.p.) also attenuated
A␤25-35 -induced amnesia [569]. Baicalin prevented
the production of hydrogen peroxide and oxidative
stress induced by A␤ aggregation in SH-SY5Y cells
[570]. Apigenin (4 ,5,7-trihydroxyflavone), baicalein,
and nordihydroguaiaretic acid were potent inhibitors
of liposome permeabilization by A␤42 oligomers
21
[571]. Baicalein inhibited the formation of ␣-synuclein
oligomers within living cells and prevented A␤ peptide
fibrillization and oligomerization [572].
Beta-asarone improved cognitive functions in rats
after injection of A␤ into the hippocampus [573] probably via JNK signaling and modulation of bcl-2 family
proteins [574] and attenuation of neuronal apoptosis
[575, 1708].
BT-11 is an extract of the dried root of Polygala tenuifolia (Willdenow) and effectively enhanced
cognitive functions in elderly humans [576–578].
BV-7003 (Bioved Pharmaceuticals) is a natural
product for the potential treatment of memory loss
(Thomson Reuters Pharma, update of September 11,
2012). The structure was not communicated.
Cabernet Sauvignon attenuated A␤ neuropathology in a mouse model of AD [579].
Carvacrol showed cognition enhancing activity in
two rat models of dementia [580].
Catechins showed potent anti-amyloidogenic and
fibril-destabilizing effects in vitro [581–583].
Celastrol, a triterpenoid antioxidant compound isolated from the Chinese Thunder of God vine (T.
wilfordii) reduced A␤ pathology in a transgenic mouse
model of AD [584].
Celastrus paniculatus seeds showed nootropic
activity [585].
Chelerythrine showed promising cholinesterase
inhibition, good inhibition of amyloid-␤ aggregation
and the ability to disaggregate preformed amyloid-␤
aggregates [1709].
Cinnamon extract reduced A␤ oligomerization and
corrected cognitive impairment in animal models of
AD [586].
Coumarins are naturally occurring ␤-secretase
inhibitors [587] and acetylcholinesterase inhibitors
[588].
Cryptotanshinone (CTS), an active component
of the medicinal herb Salvia miltiorrhiza, inhibited
A␤ aggregation and protected SH-SY5Y cells from
damage by A␤ [589]. It upregulated ␣-secretase by
activation PI3K pathway in cortical neurons [590].
Curcumin showed potent anti-amyloidogenic
effects for AD A␤ fibrils in vitro and in vivo [591–605].
Clinical trials in AD patients showed disappointing
results [350, 600, 606]. A novel nanoparticle formulation of curcumin (NanoCurc) was developed at
the Indiana University School of Medicine [607].
For curcumin-decorated nanoliposomes see [608].
Structure-activity relationships of A␤ aggregation
inhibitors based on the curcumin scaffold were presented [609–611].
22
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
DL-3-n-butylphtalide (NBP Pharmaceuticals,
Hebei China) is a natural antioxidant extracted from
seeds of Apium and a powerful free radical scavenger
[413]. It protected dopamine neurons in a rotenone
model for PD [414].
DX-9386 is a traditional Chinese medicinal
prescription, which improved thymectomy-induced
impairment of learning behaviors in mice [612].
Ecdysterones, steroidal hormones in insects and
terrestrial plants, inhibited A␤ aggregation, disaggregated preformed fibrils, and inhibited A␤42 -induced
cytotoxicity [613].
(-)-Epigallocatechin-3-gallate (EGCG; Sunphenon) present in green tea reduced A␤-mediated
cognitive impairment presumably via flavonoidmediated presenilin-1 phosphorylation, which
reduced A␤ production [614–616]. EGCG prevented
lipopolysaccharide-induced elevation of A␤ generation [617]. EGCG remodeled mature ␣-synuclein
and A␤ fibrils and reduced cellular toxicity [618].
The cell signaling pathways and iron chelation were
described [582, 619–624]. Also ERK and NF- κB
pathways are involved [617]. The structural properties
of EGCG-induced, nontoxic AD A␤ oligomers were
described [625]. EGCG functions through estrogen
receptor mediated activation of ADAM10 in the
promotion of non-amyloidogenic processing of A␤PP
[626, 627]). A special formulation of EGCG in
nanolipidic particles to improve its bioavailability was
presented [628]. See also Part 1, Chapter 1.9. Drugs
interacting with estrogen receptors and Part 1, Fig. 10.
ESP-102, a standardized combined extract of
Angelica gigas, Saururus chinensis, and Schizandra
chinenis, significantly improved scopolamine-induced
memory impairment [629] and A␤1-42 -induced memory impairment in mice [630].
An aqueous extract of Eucommia ulmoides
Oliv. Bark (EUE) showed beneficial effects on learning and memory impairments in mice [631].
Flavonoids in AD and neuroinflammation were
discussed in depth [621, 632–635]. Some act as acetylcholinesterase inhibitors [636]. Biflavanoids were
superior to monoflavonoids in inhibiting A␤ toxicity
[637].
Fortasyn Connect is a multi-nutrient diet comprising docosahexanoic acid (DHA), eicosapentenoic
acid, uridine-mono-phosphate, choline, phospholipids,
folic acid, vitamins B6, B12, C, and E and selenium. It reduced AD-like pathology in young adult
A␤PPSWE /PS1dE9 mice [638].
Fulvic acid inhibited aggregation and promoted disassembly of tau fibrils associated with AD [639].
Gallic acid from grape seed polyphenol extract may
be useful for the treatment of AD [583].
Garlic extract attenuated the cytotoxicity of A␤ on
undifferentiated PC12 cells [640] and suppressed lipid
peroxidation induced by A␤ in PC12 cells [641]. It
protected against A␤-induced apoptosis [642]. Garlic
extract inhibited A␤ fibril formation and defibrillated
A␤ preformed fibrils [643]. Aged garlic extract ameliorated the early cognitive deficits in Tg2576 mice
[644, 645]. A review on the “aged garlic extract” was
published [646].
Gastrodin protected primary cultured rat hippocampal neurons against amyloid-␤ peptide-induced
neurotoxicity via ERK1/2-Nrf2 pathway [1710].
Ginger root extracts (Zingiber officinale, Cognition Therapeutics) effected inhibition of A␤42
aggregation (Thomson Reuters Pharma, update of May
23, 2012).
Gingko biloba (EGb 761, Tanakan, Tanamin) treatment prevented age-related spatial memory deficits in
a transgenic mouse model of AD [647]. It enhanced
adult hippocampal neurogenesis and phosphorylation
of CREB [648]. For reviews on Ginkgo biloba extract
and CNS functions, see [649, 650]. For results of clinical studies, see (in chronological order) [651–665].
Grape-derived polyphenolics from Vitis vinifera
grape seeds attenuated cognitive deterioration in a
mouse model of AD [666]. Ultrastructural alterations
of AD paired helical filaments by grape seed-derived
polyphenols was studied [667].
Guanosine protected human neuroblastoma cells
from oxidative stress and toxicity induced by A␤ peptide oligomers [668].
Hederacolchidide-E from Pulsatilla koreana
showed cognition-enhancing and neuroprotective
effects by reversing scopolamine-induced cognitive
impairments in rats. It increased viability of human
neuroblastoma SK-N-SH cells incubated with A␤42
[536].
Heme prevented A␤1-40 aggregation and its cytotoxicity [669].
Hopeahainol A attenuated memory deficits by targeting amyloid-␤ in APP/PS1 transgenic mice [1711].
HSH-971 (Ocean University of China, Shandong)
is a marine sulfated oligosaccharide for the potential
treatment of AD [670]. (Thomson Reuters Pharma,
update of November 7, 2011).
HX-106 (HX-106N; ViroMed Co., Seoul) is a
natural product inhibiting acetyl-cholinesterase for
the potential treatment of AD (Thomson Reuters
Pharma, update of June 13, 2012). The structure was
not disclosed.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Hyperoside protected primary rat cortical neurons from neurotoxicity induced by A␤ via the
PI3K/Akt/Bad/Bcl(XL)-regulated
mitochondrial
apoptotic pathway [671].
IB-10C179(Instituto Biomar, Leon, Spain) is a
compound derived from marine organisms which protected primary neurons from apoptosis and reduced
free radical production (Thomson Reuters Pharma,
update of March 7, 2012). The structure was not
communicated.
Icariin is a flavonoid isolated from Epimedii
herba. It inhibited A␤25-35 induced expression of
␤-secretase in rat hippocampus [672]. It attenuated
A␤-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells [673]. It
attenuated lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting
TAK1/IKK/NF-κB and JNK/p38 MAPK pathways
[674]. It improved memory impairment in AD model
mice and attenuated A␤-induced neurite atrophy [675].
There seems to be a synergistic effect to improve learning and memory deficits in rats by co-administration
of Icariin and Panax notoginseng saponins [676].
IDN-5706, a hyperforin derivative, decreased the
content of acetylcholinesterase associated with different types of A␤ plaques in 7-month-old double
A␤PPSWE /PS1 transgenic mice after treatment with
IDN 5706 for 10 weeks [677].
Kaempferol protected PC12 and T47D cells from
A␤ toxicity [581, 678, 679].
Loganin isolated from Cornus officinalis showed
cognitive-enhancing activity in scopolamine-induced
amnesic mice [680].
Luteolin exerted ameliorating effects on A␤induced impairment of water maze performance and
passive avoidance in rats [681–684].
Medical Food Cocktail consisting of the dietary
supplements curcumin, piperine, epigallocatechin gallate, ␣-lipoic acid, N-acetylcysteine, B vitamins,
vitamin C, and folate administered for 6 months to
Tg2576 mice resulted in improvement of cognitive
functioning [685].
Melatonin inhibited AD ␤-fibrillogenesis
[686–689]. The neuro-protective activities of
melatonin against the A␤ are not mediated by melatonin membrane receptors. The role of melatonin in
AD-like neurodegeneration was described [690–693].
Melatonin facilitated short-term memory [694].
Menthol exerted a protective effect on A␤-induced
cognitive deficits in mice [695].
Morin destabilized A␤42 protofibrils [696]. It inhibited the early stages of A␤ aggregation [697]. It
23
attenuated tau hyperphosphorylation by inhibiting
GSK-3␤ [698].
Myrcetin is a naturally occurring regulator of metalinduced A␤ aggregation and neurotoxicity [699, 700].
Naringin showed memory enhancing activity in
mice [701].
NeurocentRX Pharma is investigating a natural
product-based compound for the treatment of cognitive
diseases (Thomson Reuters Pharma, update of February 17, 2012).
Nordihydroguaiaretic acid inhibited growth arising from direct A␤ protofibril association [599, 702,
703].
O4 (an orcein-related small molecule) was able to
convert toxic A␤ oligomers to nontoxic ␤-sheet-rich
amyloid fibrils [704].
Obovatol, a biphenolic compound isolated from
Magnolia obovata, attenuated scopolamine-induced
cognitive dysfunctions [705], improved cognitive
functions in animal models of AD [706], and
attenuated LPS-induced memory impairments in mice
via inhibition of NF-κB signaling pathway [707, 708].
Oleuropein and derivatives from olives were recognized as tau aggregation inhibitors [709].
Oren-gedoku-to exerts its potential use for the
treatment of AD as a weak, reversible inhibitor of
indoleamine-2,3-dioxygenase [710].
Oroxylin A is a flavonoid compound that is found in
the root of Scutellaria baicalensis Georgi. It attenuated
the memory impairment induced by transient bilateral
common carotid artery occlusion in mice [711].
1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose
is the active constituent of the traditional medicinal
herb Paeonia suffruticosa. It showed potent A␤
anti-aggregation effects in vitro and in vivo [712].
Piceatannol showed protective effects against A␤induced neuronal cell death [713].
Pinocembrin, a flavonoid abundant in propolis, protected against A␤-induced toxicity in neurons [714].
Polyphenol derivatives (Pharma Eight, Nagoya)
probably interacted with A␤ through ␲ – ␲ stacking
interactions via the aromatic amino acids of A␤ [715].
For a review, see [716] (Thomson Reuters Pharma,
update of January 13, 2011).
Procyanidins extracted from the lotus seedpod
reversed memory impairment in cognitively impaired
aged rats associated with decreased hippocampal
CREB phosphorylation [717, 718].
Prosopis cineraria (L.) Druce (Leguminosae), a
plant of the Thar Desert of India and Pakistan, is used
traditionally by local people for the treatment of memory disorders and to arrest wandering of the mind.
24
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
The extract exerted significant nootropic activity in the
Morris water maze test, which may be attributed to the
inhibition of brain acetylcholinesterase [719].
Puerarin, a phytoestrogen isolated from Pueraria
lobata, attenuated A␤-induced cognitive impairment
[720–723, 1712].
Quercetin-O-glucuronide significantly reduced the
generation of amyloid-␤ peptide [1713].
Pycnogenol protected neurons from A␤-induced
apoptosis [724].
Quercetin showed protective effects against A␤42
in primary neurons [586, 725]).
Rosmarinic acid protected PC12 cells from
A␤-induced neurotoxicity [599, 726]. Subchronic
administration of rosmarinic acid, a natural prolyl
oligopeptidase inhibitor, enhanced cognitive performance [727].
Rutin inhibited A␤ aggregation and cytotoxicity,
attenuated oxidative stress, and decreased the production of nitric oxide and proinflammatory cytokines
[728].
Saffron from Crocus sativus had an inhibitory effect
on A␤ aggregation [729, 730]. It was administered
to 46 patients with probable AD in a 16-week double blind study (15 mg twice a day). Saffron was safe
and effective [731]. A 22 week study corroborated the
first results [732]. Saffron may be a source of novel
acetylcholinesterase inhibitors [733].
Salidroside showed neuroprotective effects against
A␤-induced oxidative stress in SH-SY5Y human neuroblastoma cells [734].
S-allyl-L-cysteine, the main constituent of garlic,
protected against A␤-induced apoptosis and attenuated
caspase-3 activation, DNA fragmentation and PARP
cleavage [648]. It exerted protective effects on A␤induced cell death in NGF-differentiated PC12 cells
[735] and protected against A␤-induced neurotoxicity in organotypic hippocampal cultures [736]. For a
review on garlic extract and one of its active ingredients, S-allyl-L-cysteine, see [646].
Silibinin, a flavonoid derived from Silybum marianum, prevented memory impairment induced by
A␤25-35 in the Y-maze and novel object recognition
tests in mice [737].
Sinapic acid is a phenylpropanoid compound with
anti-inflammatory and neuroprotective effects in a
mouse model of A␤1-42 protein-induced AD [738].
Souvenaid (Nutricia, Châtel-St-Denis, Switzerland) is a mix of nutrients including the omega-3
fatty acid docosahexanoic acid, uridine monophosphate, and choline, dietary precursors for the synthesis
of phospholipids. Two clinical trials, Souvenir I, which
lasted 12 weeks, and Souvenir II, which lasted 24
weeks, were concluded [739–741].
Substance P, the tachykinin undecapeptide, protected cerebellar granule cells against A␤-induced
apoptosis [742].
Syringin from the dried stem barks of Fraxinus
rhynchophylla protected against A␤-induced toxicity
in neuronal cells [743].
Tannic acid destabilized A␤ fibrils in vitro [744,
745]. It is a natural ␤-secretase inhibitor [746].
␣-Tocopherol quinone inhibited A␤ aggregation
and cytotoxicity, disaggregated preformed fibrils and
decreased the production of ROS, nitric oxide, and
inflammatory cytokines [747].
Thymol showed cognitive-enhancing activity in two
rat models of dementia [580].
Total coptis alkaloids produced a protective effect
on A␤25-35 -induced learning and memory dysfunction
in rats [748].
Ursolic acid attenuated A␤-induced apoptosis in a
dose dependent manner [749].
Vitamin A has anti-oligomerization effects on A␤
in vitro [750].
Vitamin B12 deficieny is associated with cognitive
impairment [1714]. Vitamin B12 supplements administered orally or parenterally at high dose (1 mg daily)
were effective in correcting biochemical defiency, but
improved cognition only in patients with pre-existing
vitamin B12 deficiency [1715].
Vitamin D defiency is associated with increased
odds of cognitive impairment [1716–1718].
Withania somnifera (also known as Ashwagandha,
an Indian ginseng) is a nootropic agent promoting
cognition including memory [751]). W. somnifera
administered once daily over 30 days reversed behavioral deficits, plaque pathology, accumulation of A␤
peptides and oligomers in the brains of middle-aged
and old A␤PP/PS1 AD mice. Enhanced expression of
low-density lipoprotein receptor-related protein (LRP)
in brain microvessels and the A␤ degrading protease
neprilysin occurred 14–21 days after a substantial
decrease in brain A␤ levels [752].
Wuzi Yanzong Granule improved memory functions in patients with MCI [753].
Yokukansan (TJ-54), a traditional Japanese herbal
medicine, was tested in clinics for potential antidementia effects [754]. Spatial memory in a rat model
of early AD was improved [755].
Zokumei-to (ZMT) attenuated A␤25-35 -induced
memory impairment [756].
The Central Drug Research Institute (India) was
developing bacosides A and B, which are saponin
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
nootropic agents. The compounds were in Phase II
clinical evaluation, but it appears that the development
was terminated. Also the development of CBNU06 (Chungbuk University), DCB-AD1 (Development
Center for Biotechnology), dysiherbaine (Daiichi
Suntory Biomedical Research Co., a compound isolated from the Micronesian sponge Dysidea herbacea
[757]), of the nordihydroguaiaretic acid derivative
EM-4232 (Eromos Pharmaceutical LLC), HSS808, HSS-818, HSS-838, HSS-848 and HSS-888
(HerbalScienceLLC Singapore; standardized turmeric
curcuma longa extracts), of LHM-123 (Mazal Plant
Pharmaceuticals), MDF-004 and MDF-005 (Neuron
BioPharma), and of YY-1224 and YY-1824 (Yuyu;
orally available terpene trilactones extracted from
Ginkgo biloba [758]) was terminated.
NOOTROPICS (“DRUGS WITHOUT
MECHANISM”)
In this chapter compounds are described, whose
mechanism(s) of action are unknown. Initiation of clinical trials was based on positive effects on impaired
brain functions in experimental animals after proof of
good tolerability.
LSL-001 (Laboratoire S. Lasnier, Etaules, France)
is a nootropic compound in Phase II clinical trials since
June 2011 for the potential treatment of AD (Thomson
Reuters Pharma, update of June 5, 2012). The structure
was not disclosed.
N-251 (Neurokos Inc., Palo Alto, CA) is a compound of an undisclosed mechanism of action for
the potential treatment of AD. Phase II clinical trials
started in May 2009 (Thomson Reuters Pharma, update
of January 16, 2012). The structure of N-251 was not
communicated.
PF-03049423 (Pfizer) is a neurorestorative compound for the potential treatment of neurological
disorders including stroke recovery. In December
2010, a randomized, double-blind, placebo-controlled
Phase II trial was initiated in the US and in South Korea
(n = 240) (Thomson Reuters Pharma, update of August
13, 2012). The structure was not communicated.
TPM-189 (Teikoku Pharma USA, San Jose, CA) is
a transdermal formulation of a small molecule therapeutic for the potential treatment of AD in Phase
II development (Thomson Reuters Pharma, update of
May 17, 2012). The structure was not communicated.
VI-1121 (VIVUS Inc., Mountain View, CA) is a
nootropic agent in Phase II clinical trials (n = 50) since
August 2011 in the US (NCT01428362) (Thomson
25
Reuters Pharma, update of September 9, 2011). The
structure of VI-1121 was not communicated.
ASP-0777 (Astellas Pharma) is in Phase I clinical trials since May 2009 (Thomson Reuters Pharma,
update of September 19, 2012). The structure was not
disclosed.
Lilly is developing a small molecule for the treatment of cognitive impairment in schizophrenia in
Phase I clinical trials since July 2012. (Thomson
Reuters Pharma, update of November 13, 2012). The
structure was not disclosed.
RO-5508887 (Roche) is a nootropic agent in
Phase I clinical trials in healthy male volunteers in
France since October 2011 (Thomson Reuters Pharma,
update of August 16, 2012). The structure was not
disclosed.
SEP-363856 (Sunovion Pharmaceuticals, Marlborough MA and Sumitomo Chemical) is an orally active
compound with novel mechanism of action for the
treatment of schizophrenia. The drug is in Phase I in the
US. (Thomson Reuters Pharma, update of November
5, 2012). The structure was not disclosed.
TAK-357 (Takeda) is a cognitive enhancer with
unspecified drug target in Phase I clinical development
(Thomson Reuters Pharma, update of July 30, 2012).
The structure was not communicated.
There are currently many nootropic agents in preclinical evaluation (in alphabetical order):
AC-0523 (Neuera, a subsidiary of Accera, Broomfield, CO) (Fig. 11) is indicated for the treatment
of mitochondrial dysfunction-related HD (Thomson
Reuters Pharma, update of February 15, 2012).
AFX-929 (Afecta Pharmaceuticals; Irvine, CA) is a
nootropic agent in preclinical development (Thomson
Reuters Pharma, update of November 10, 2011). The
structure was not disclosed.
Alzheimer’s disease therapeutics (Berg Pharma,
Nashville TN) are nootropic compounds for the potential treatment of AD (Thomson Reuters Pharma,
update of April 17, 2012). The structures were not
disclosed.
Alzheimer’s disease therapeutics (SienaBiotech/
Roche) are neuroprotectant compounds for the potential treatment of AD (Thomson Reuters Pharma,
update of February 8, 2012). The structures were not
disclosed.
Alzheimer’s disease therapy (Reyon Pharmaceuticals, Seoul) is a therapeutic program for the potential
treatment of AD (Thomson Reuters Pharma, update of
June 20, 2012). The structures were not disclosed.
AVN-457, AVN-458, and AVN-492 (Avineuro Pharmaceuticals, San Francisco, CA) are nootropic agents
26
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 11. Nootropics and one peptide.
in preclinical development (All three drugs in Thomson Reuters Pharma, update of August 19, 2011). The
structures were not disclosed.
CPC-001 (Chase Pharmaceuticals, Washington,
DC) is a compound for the palliative treatment of AD
(Thomson Reuters Pharma, update of July 12, 2012).
The structure was not communicated.
CWF-0804 (JW Pharmaceutical Corp., Choongwae
Holdings, Seoul) is a nootropic agent in development for the Korean and Japanese markets (Thomson
Reuters Pharma, update of May 11, 2012). The structure was not disclosed.
D-130 (Envoy Therapeutics, Jupiter, FL) is a compound targeting the cortex region of the brain using
bacTRAP technology for the potential treatment of
cognition deficits (Thomson Reuters Pharma, update
of June 1, 2012). The structure was not disclosed.
D-180 (Envoy Therapeutics, Jupiter, FL) is a compound targeting the striatum region of the brain using
bacTRAP technology for the potential oral treatment
of PD (Thomson Reuters Pharma, update of September
12, 2012). The structure was not disclosed.
GSK-2647544 (GSK) is a neuroprotectant for the
potential treatment of Alzheimer’s disease. In October
2012, a single-blind, randomized, placebo-controlled,
Phase I trial was expected to begin later that month in
Australia in healthy male subjects (expected n = 16). At
that time, the trial was expected to complete in April
2013 (Thomson Reuters Pharma, update of November
20, 2012). The structure was not disclosed.
J-147 (Salk Institute for Biological Studies)
(Fig. 11) is a drug that improved memory in normal
rodents and prevented cognitive decline in transgenic
mice of AD (Thomson Reuters Pharma, update of
December 22, 2011).
JAY 2-22-33 (Medical College of Georgia) (Fig. 11)
significantly reduced A␤ toxicity and improved cognitive performances in transgenic AD mice [759].
JWB1-84-1 (Medical College of Georgia) (Fig. 11)
is a tertiary amine analogue of choline from the laboratory of the late Prof. Jerry J. Buccafusco. It produced a
dose-dependent decrease in the number of errors made
by well-trained AD-transgenic mice in the radial arm
water maze test [759, 760].
KD-901 (Kwang Dong Pharmaceutical Co., Seoul)
is a nootropic drug in preclinical evaluation (Thomson Reuters Pharma, update of March 1, 2011). The
structure was not disclosed.
KU-046 (Kareus Therapeutics and Connexios Life
Sciences, Atlanta, GA) is a combination drug, which
demonstrated significant improvement of cognition
(Thomson Reuters Pharma, update of May 29, 2012).
The structure was not disclosed.
LNK-3186 and LNK-3248 (AstraZeneca after its
acquisition of Link Medicine Corp., Waltham, MA)
are nootropic compounds (For both Thomson Reuters
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Pharma, update of July 13, 2012). The structures were
not disclosed.
Maltoyl p-coumarate attenuated cognitive deficits
in rats treated with scopolamine or with A␤42 [761].
MeN061016-1 (Lijun International Pharmaceutical, Hong Kong) is a small molecule neuroprotectant
(Thomson Reuters Pharma, update of June 26, 2012).
The structure was not disclosed.
MPP-26 (M et P Pharma, formerly Mattern Pharmaceuticals, Emmetten, Switzerland) is an intranasal gel
formulation of pregnenolone for the potential enhancement of memory (Thomson Reuters Pharma, update of
January 27, 2012).
NNZ-2591 (Neuren Pharmaceuticals, Auckland,
NZ) (Fig. 11) is an orally active neuroprotectant diketopiperazine derivative for the treatment of brain injury
and PD [762] (Thomson Reuters Pharma, update of
August 31, 2012).
NXD-9062 (Nymox Pharmaceutical Corp., Quebec)
is a neuroprotectant for the potential treatment of AD
(Thomson Reuters Pharma, update of February 22,
2012). The structure was not disclosed.
NXT-182 (Inception Sciences Inc., San Diego) is
a novel small molecule neuroprotectant for the potential treatment of CNS disorders, including Alzheimer’s
disease, Parkinson’s disease and age-related cognitive
decline (Thomson Reuters Pharma, update of October
29, 2012). The structure was not disclosed.
OG-635 (Oryzon Genomics, Barcelona) is a
nootropic agent for the potential treatment of AD and
PD (Thomson Reuters Pharma, update of May 31,
2012). The structure was not disclosed.
Pentylenetetrazole (Balance Therapeutics, Hillsborough, CA) is investigated for the potential treatment
of cognitive impairment in Down’s syndrome (Thomson Reuters Pharma, update of September 4, 2012).
PNB-03, PNB-04, and PNB-05 (PharmaNeuroBoost NV, Limburg, Belgium) are nootropic agents for
the potential treatment of PD (PNB-03), AD (PNB-04),
and obsessive compulsive disorders (PNB-05) (Thomson Reuters Pharma, update of February 1, 2012). The
structures were not communicated.
PTI-125 (Pain Therapeutics Inc., Austin, TX)
reduced A␤-related AD pathogenesis by targeting filamin A [763] (Thomson Reuters Pharma, update of
August 3, 2012). The structure was not communicated.
RP-4000 (Reviva Pharmaceuticals, San Jose, CA)
is a small molecule nootropic agent (Thomson Reuters
Pharma, update of December 27, 2011). The structure
was not communicated.
SEL-103 (Selvita Life Sciences Solutions, Krakow,
Poland and Orion, Espoo, FL) is a program inves-
27
tigating small molecule nootropic agents (Thomson
Reuters Pharma, update of July 4, 2012). Structures
were not communicated.
SKL-A4R (SK Biopharmaceuticals, formerly SK
Life Science, Fair Lawn, NJ) is a small molecule
nootropic agent (Thomson Reuters Pharma, update of
March 19, 2012). The structure was not communicated.
TYP-1 (NOBEL ILAC, Istanbul, Turkey) is a small
molecule neuroprotectant (Thomson Reuters Pharma,
update of July 30, 2011). The structure was not communicated.
The development of ABIO-08-01 (BTG-1640;
Abiogen under license from British Technology
Group, BTG), ADS-8703 (Adamas Pharmaceuticals),
AIP-002 (American Home Products, Wyeth, now
Pfizer), AIT-034 (Spectrum Pharmaceuticals, formerly
NeoTherapeutics), Alzheimer’s disease therapeutics
(DuPont/Scios), ALE-26015 (Allelix Pharm-Eco LP),
aloracetam (Hoechst, now sanofi), Alzene (Bar Ilan
University and Ivax); AQW-051 (Novartis; Phase II
trials for treatment of schizophrenia and PD are ongoing), ASP-2535 and ASP-2905 (Astellas), AVN-397
(Avineuro Pharmaceuticals; in Phase II trials for the
treatment of anxiety), AWD-52-39 (Alzneimittelwerke Dresden, elbion), AZD-2858 (AstraZeneca),
BCE-001 (4-chloro-phenoxy-acetic acid-1,3-bis
(dimethylamino)-2-propylester [764–766]), BD-1054
(Russian Academy of Medical Science), BGC-200406 (RS-0406; SEN-1269 [767]; Senexis under
license from BTG under license from Sankyo), BGC20-0466 (BTG), BGC-20-1178 (Senexis under license
from BTG under license from Sankyo), BGC-20-1259
(BTG under license from Sankyo), BMS-181168
(BMY-21502; Bristol-Myers Squibb [768–770]),
BTG-4247 (BTG), BW-394-U (GSK), CG-301338
(CrystalGenomics), CL-287663 (KE-748; Lederle
Laboratories, now Pfizer), of CLL-502 (CLL Pharma),
CM-2433 (Cenomed, a subsidiary of Abraxis BioScience in collaboration with Medical College of
Georgia), CX-417, CX-423 and CX-438 (Cortex
Pharmaceuticals), DW-514 and DW-0811 (Daewon
Pharm), DWJ-209 (Daewoong Pharmaceutical Co.),
of the coumarin derivative ensaculin (KA-672;
Dr. Willmar Schwabe [771–777]), ETX-6765 (eTherapeutics), F-94517 (Pierre Fabre), gedocarnil
(Bayer Schering Pharma), GM-1416 (GliaMed Inc.),
GT-4035 and GT-4054 (Gliatech), HL-026 (HanAll
Biopharma), HMR-2420 (Hoechst Marion Roussel,
now sanofi), HSB-13 (EncephRx, a spin-out of the
Southern Methodist University and the University of
Texas [1719]), HTC-867 (Wyeth, now Pfizer), IQ200
and IQ-201 (Immune Network under license from
28
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
the University of British Columbia), JNJ-39393406
(Janssen Pharmaceutica), LX-104 (Laxdale, Amarin
Corp.), of the MBARC program (EnVivo Pharmaceuticals), MK-0249 (Merck & Co), MK-5757
(Merck & Co), MG-19649 (Molecular Geriatrics,
now Applied Neuro Solutions), MP-100 (Addiction
Therapeutix), MR-708 (Medea Research), NDD-094
(Novartis [778]), NeoEA-1001 (neoCodex), nooglutil
(Russian Academy of Medical Sciences [779]), NSA789 (Wyeth, now Pfizer), OF-5858 and OF-6145 (All
Russian Research Institute of Pharmaceutical Chemistry), Oligotropin (HF-0420; Loyola University of
Chicago), Org-31433 (Organon Biosciences, now
MSD OSS BV), PF-05297909 (Pfizer), Prisotinol
(CGS-5649B; Ciba-Geigy, Novartis [780–783]), procaine hydrochloride (Samaritan Pharmaceuticals),
PRX-4001 and PRX-4006 (Proximagen), R-641 and
Ro-40-1641 (both Roche), RU-47067 and RU-52583
(Roussel-Uclaf, now sanofi), sabeluzole (Janssen
Pharmaceutica NV, Johnson & Johnson [784–789]),
SCH-54388 (Schering-Plough, now Merck; a metabolite of felbamate), sibopirdine (EXP921; Du Pont
Merck [790]), silicon-containing pyridylsubstituted
isoxazoles (Latvian Institute of Organic Synthesis),
SLV-351 (Solvay Pharmaceuticals, now Abbott
Laboratories), SN-104 (Sention), SNK-882 (Sanwa
Kagaku Kenkyusho), SPPI-339 (SPI-339, NEO-339;
Spectrum Pharmaceuticals, formerly NeoTherapeutics), SRA-997 (Novartis), ST-587 (Boehringer
Ingelheim), T-9021 and T-9022 (QRxPharma), TAK065 (Takeda), tenilsetam (Hoechst Marion Roussel,
now sanofi [791, 792]) trifusal (Grupo Uriach),
V-0191 (Pierre Fabre) and of Z-4105 (Zambon) was
terminated.
PEPTIDES
Cerebrolysin (Ebewe Pharmaceuticals, Vienna,
Austria, launched, available in 1 ml, 5 ml, and 10 ml
ampoules and in vials of 30 ml and 50 ml for intramuscular or intravenous injection or intravenous infusion)
is “derived through a biotechnological procedure from
highly purified porcine brain proteins and is comprised of free amino acids and biologically active,
short chain peptides” [793]. Cerebrolysin acted as
a presynaptic GABAB receptor agonist [794]. The
nootropic effects of cerebrolysin were investigated in
depth [795–799]. Cerebrolysin protected neurons from
ischemia-induced loss of microtubule-associated protein 2 [800]. Effects of cerebrolysin on A␤ deposition
in transgenic mice were studied extensively [801–807].
The pharmacology of neurotrophic treatment with
cerebrolysin was reviewed [808]. Clinical data were
published (in chronological order) [793, 809–823].
First clinical results of a combination treatment of cerebrolysin and donepezil were reported [824]. Data of
cerebrolysin in AD were compiled [825]. The safety
profile of cerebrolysin in dementia and stroke trials was
described [826].
Cortexin (Geropharm, St. Peterburg, Russia)
is a launched polypeptide with neuroprotective,
nootropic and antioxidant properties, for the intramuscular treatment of central nervous system injury
caused by cerebrovascular accidents, encephalitis,
encephalopathies, epilepsy and trauma (Thomson
Reuters Pharma, update of October 05, 2012). The
structure was not communicated.
Davunetide (intranasal, AL-108, NAP, Allon Therapeutics, Vancouver) is an 8-amino acid peptide
(NAPVSIPQ) derived from the activity-dependent
neuroprotective protein. A Phase III clinical trial was
initiated for the treatment of patients with progressive supranuclear palsy in December 2010. A Phase
II clinical trial in AD patients started in January 2007
(Thomson Reuters Pharma, update of July 17, 2012).
Allon Therapeutics is also developing injectable intravenous and subcutaneous formulations of davunetide.
There are numerous publications on the extensive
preclinical characterization of davunetide describing protection of the brain against ischemic injury
in rats [827], inhibition of the aggregation of A␤
[828], decrease of anxiety-like behavior in aging mice
[829], reduction of the severity of traumatic head
injury [830], reduction of accumulation of A␤ and
of tau hyperphosphorylation [831–833], stimulation
of microtubule assembly [834, 835], enhancement
of cognitive behavior in transgenic mice [836]),
and improvement in motor function and reduction
of ␣-synuclein inclusions in mice overexpressing
␣-synuclein [837]. Reviews on davunetide were
published [838–847]. The effects of davunetide on cognition and functional capacity in schizophrenia were
described [848] (Thomson Reuters Pharma, update of
September 21, 2012).
AM-111 (XG-102, D-JNKI-1; Auris Medical and
Xigen, a spin off from the Centre Hospitalier Universitaire Vaudois and the University of Lausanne) is
an injectable protease-resistant peptidic derivative of
the JNK-inhibiting protein IB-1 for the i.v. treatment
of acute sensorineural hearing loss, stroke, and AD
[849–852]. A Phase IIb trial for acute sensorineural
hearing loss was initiated in January 2009 (n = 210) and
results are expected in autumn of 2012. Auris Medical
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
is also investigating a topical gel formulation of AM111 (Thomson Reuters Pharma, update of August 31,
2012).
Etanercept (ENBREL, NK-001; Neurokine Pharmaceuticals, Vancouver) is a recombinant fusion
protein of 934 amino acids (mol. weight: 150 kDa)
composed of a dimer of the extracellular portion of
human TNFR-2 fused to the Fc fragment of human
IgG1 [853, 854]. A rapid cognitive improvement
following perispinal etanercept administration to 15
probable-AD patients treated once weekly for 6 months
was reported [855–857]. See also the commentary
[858]. In December 2010, the drug was in Phase II
development for the potential treatment of neurocognitive impairment following coronary artery bypass graft
surgery (Thomson Reuters Pharma, update of July 9,
2012).
FGL (ENKAM Pharmaceuticals, Copenhagen,
Denmark) is a peptide neural cell adhesion molecule
mimetic for the potential treatment of AD and stroke.
In December 2011, clinical studies including three
Phase I studies, one proof-of-concept Phase IIa study
in AD, and a pilot study in patients recovering from
stroke was planned to begin in 2012 (Thomson Reuters
Pharma, update of April 23, 2012). Enkam was previously developing FGLL, a peptide neural cell adhesion
molecule mimetic, for the potential intranasal treatment of AD and stroke. In May 2005, the drug was
shown to be safe and well tolerated in a Phase I study
for AD. By December 2011, the drug was no longer
being developed due to the lack of flexibility for the
route of administration.
Glypromate (Gly-Pro-Glu) is naturally cleaved
from the N-terminal sequence of IGF-I and displayed
neuroprotective actions in vitro and in vivo [859–861].
It protected against A␤-induced somatostatin depletion
in rat cortex [862, 863].
NNZ-2566 (Neuren Pharmaceuticals, Auckland,
NZ) (Fig. 11) is an analogue of glypromate with
an additional ␣-methyl-group on the proline moiety,
which resulted in an improved half-life and better
oral bioavailability. In March 2012, a randomized,
double-blind, placebo-controlled Phase I study was
initiated in healthy volunteers (n = 32) in Australia.
Potential indications are mild traumatic brain injury,
Rett syndrome, PD, and AD [864– 867]. Excellent synthetic organic chemistry was described [868–871]. In
November 2012 the IND was filed for a Phase II trial.
At that time an application was submitted to the Texas
Children’s Hospital IRB and enrollment was expected
to begin pending approval by the FDA and the Texas
Children’s Hospital IRB. (Thomson Reuters Pharma,
29
update of November 23, 2012). (Thomson Reuters
Pharma, update of August 31, 2012). Neuren is also
developing a formulation for intravenous infusion.
There are many peptides in preclinical evaluation for
the potential treatment of AD (in alphabetical order):
AL-408 (Allon Therapeutics, Vancouver) is the
orally active D-amino acid derivative of davunetide (AL-108) and an active element of the PARP-1
activating activity-dependent neuroprotective protein
(Thomson Reuters Pharma, update of November 9,
2011).
Alzimag (IMAGENIUM, Paris, France) is a peptide
for the potential treatment of AD (Thomson Reuters
Pharma, update of December 22, 2011). The structure
of the compound were not communicated.
C3bot peptides (Charité Medical School Berlin and
Hannover Medical School) are short neuron-specific
neuritogenic peptides derived from the C3 exoenzyme
of Clostridium botulinum, which transiently activated
RhoA for the potential treatment of neurodegenerative disorders including AD, PD, Huntington’s chorea,
spinal cord and traumatic brain injury [872–875]
(Thomson Reuters Pharma, update of June 7, 2012).
COG-112, COG-133, and COG-1410 (Cognosci
Inc., Research Triangle Park, NC) are apoE-mimetic
peptides that showed consistent reduction of both A␤
deposition and of tau hyperphosphorylation in three tau
transgenic mouse models and in two A␤PP transgenic
mouse models [876, 877] (Thomson Reuters Pharma,
update of June 5, 2012 for COG-112 and of September
11, 2012 for COG-133 and COG-1410).
G-79 (BN-201; Bionure, Barcelona) is a peptide for
the potential treatment of multiple sclerosis, ALS, AD,
PD, and glaucoma (Thomson Reuters Pharma, update
of July 4, 2012).
KIBRA pathway modulators (Amnestix Inc., a
wholly owned subsidiary of SYGNIS Pharma; Heidelberg, Germany) offer a new genetic link to cognition
that may benefit patients suffering from AD. For the
association of KIBRA and late onset AD, see [878];
for enhancement of cognition in anxiety disorders
[879] (Thomson Reuters Pharma, update of August
14, 2012).
Leptin reduced the accumulation of A␤ and phosphorylated tau in rabbit organotypic slices [880–882].
The company Neurotez (Bridgewater, NJ) is investigating leptin as an A␤ synthesis inhibitor for the
potential treatment of AD. The company planned to
file an IND in 2012. Effects of leptin on memory
processing were described [883–885]. Leptin induced
proliferation of neuronal progenitor cells [886] (Thomson Reuters Pharma, update of August 24, 2012).
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
MT-007 (MT-007-LRPIV; recombinant LRP fragments; Socratech LLC, Rochester NY) is produced by
stable transfected baby hamster kidney cells expressing LRP-IV. The preparation improved cerebral blood
flow, learning and memory in a mouse model of AD
(Thomson Reuters Pharma, update of April 23, 2012).
Netrin-1 (BioMarin Pharmaceuticals, Novato, CA,
under license from the Buck Institute) interacted with
A␤PP and regulated A␤ production [887, 888]. Netrin1 increased soluble A␤PP␣ and decreased A␤1-40
and A␤1-42 levels in a J20 mouse model of AD.
An intranasal delivery is planned (Thomson Reuters
Pharma, update of July 20, 2012).
NNZ-4921 and NNZ-4945 (NRP-2945, an 11-mer;
CuroNZ under license from Neuren Pharmaceuticals,
Auckland, NZ) are neuronal regeneration peptides for
the potential treatment of multiple sclerosis and motor
neuron disease, respectively [889] (Thomson Reuters
Pharma, updates of June 18, 2012 and September 7,
2012, respectively).
NRG-101 (Mind-NRG, Geneva, Switzerland under
license from ProteoSys, Mainz, Germany) is an
injectable neuregulin peptide for the potential treatment of PD, AD, and schizophrenia (Thomson Reuters
Pharma, update of July 6, 2012).
NT-1 and NT-2 (Neurotez, Bridgewater, NJ) are
small peptides, which block the interaction between
mutant presenilin and cytoplasmic linker protein 170
(CLIP-170) that is linked to increased A␤ levels (Both
Thomson Reuters Pharma, update of June 6, 2012).
NX-210 (Neuronax, Saint Beauzire, France) is the
lead compound of a series of peptides for the potential
treatment of spinal cord injury and other neurological
disorders, such as stroke, AD, PD, and traumatic brain
injury (Thomson Reuters Pharma, update of June 29,
2012). The structure was not communicated.
Pepticlere (DP-68 and DP-74; ProteoTech, Kirkland, WA) is the name of small molecule nasal sprays,
6- to 9-mer peptides that inhibit A␤ fibril formation (Thomson Reuters Pharma, update of August 22,
2012). The structures were not disclosed.
PP-0301 (Hybio Pharmaceutical, Guangdong,
China) is a polypeptide for the potential treatment AD
(Thomson Reuters Pharma, update of September 20,
2011).
RAP-310 (Rapid Pharmaceuticals, Zug, Switzerland) is a small stabilized receptor active peptide
targeting the CCR5 receptor for the potential treatment
of AD (Thomson Reuters Pharma, update of October
1, 2012). The structure was not communicated.
RG-01, RG-09, and RG-018 (ReGen Therapeutics,
London) are neuroprotectant peptides from colostrinin
(vide infra) for the potential treatment of neurodegenerative diseases including AD (Thomson Reuters
Pharma, update of June 27, 2012). The structures were
not communicated.
SX-AZD1 (Serometrix, Pittsford, NY) is a peptide
mimetic interacting with APOE4 (Thomson Reuters
Pharma, update of July 29, 2011). The structure was
not communicated.
XD4 is a heptapeptide isolated from a Ph.D.-C7
library through phage display that rescued memory
deficits in AD transgenic mice by significantly inhibiting A␤42 -induced cytotoxicity, increasing microglial
phagocytosis of A␤, and decreasing A␤-induced generation of ROS and nitric oxide [890].
Colostrinin (ReGen Therapeutics, London) is a
polypeptide complex isolated from ovine colostrum
containing a high proportion of proline (25%) and
hydrophobic amino acids (40%). It is composed of
peptides of molecular mass up to 3,000 Da. It reduced
aggregation of A␤ [891, 892] and alleviated A␤induced toxicity [893]. It facilitated learning and
memory in rats [894] and chicks [895]. Effects on gene
expression were described [896]. Clinical results were
presented (in chronological order) [897–901]. Reviews
on colostrinin were published [902, 903].
The development of colostrinin for the treatment
of AD patients was discontinued. The compound was
launched as a nutraceutical in Australia in July 2007
(Thomson Reuters Pharma, update of May 17, 2011).
The development of ANA-1 and ANA-5 (Alzhyme
Pty; phage peptides, which bind to A␤ to inhibit its generation of hydrogen peroxide [904]), adrenomedullin
peptides (National Institutes of Health), AS-602704
(Merck Serono under license from Axonyx), C-AVP(4-9) (Yakult Central Institute for Microbiological
Research), ebiratide (Hoe-427; Hoechst, now sanofi;
an ACTH (6-9) derivative [905–907]), gilatide
(a nonapeptide of Axonyx under license from
Thomas Jefferson University), metallothionein (Neurosciences Victoria and the University of Tasmania
[908, 909]) and of noopept (GVS-111, SGS-111;
DVD-111; Saegis Pharmaceuticals under license from
the Russian Academy of Sciences; a nootropic
dipeptide analogue of piracetam [910–920]) was
terminated. The development of NC-1900 (Nippon Chemiphar, the active fragment analog of
arginine vasopressin [921–925]), PR-21C (Pharmaxon; a polysialylated form of the neural cell
adhesion molecule) and of RGX-100 and RGX200 (RemeGenix Inc., Cortica Neuroscience; A␤
production-inhibiting BRI2-derived peptides for the
intranasal administration to AD patients [926–933])
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
was discontinued. The development of SEM-606 (University of Manchester) and of TKP-1001 (EUSA
Pharma, formerly Tasliker under license from The
Open University) was terminated.
DRUGS PREVENTING AMYLOID-␤
AGGREGATION
Plasma A␤ levels can be linked directly to specific cognitive changes that constitute the conversion
from MCI to AD [934–939]. The relationship between
atrophy and A␤ deposition in AD was investigated
thoroughly [940–942]. A review of the literature correlating Alzheimer disease neuropathologic changes
with cognitive status was provided [947]. The molecular and neurophysiological mechanisms of amyloid-␤
and cognition in Alzheimer’s disease were outlined
[1720]. A rapid decline of memory in healthy older
adults with high amyloid-␤ load was described [1721],
which was more important than ApoE genotype
[1722]. Cognitive decline in adults with high amyloid␤ load was evaluated [1723]. A␤ assemblies mediated
rapid disruption of synaptic plasticity and memory
[943]. The topic “A␤ toxicity in Alzheimer’s disease”
was reviewed [944, 945]. A critical review on the amyloid cascade hypothesis was published [946]. Although
A␤ plaques may play a key role in AD pathogenesis,
the severity of cognitive impairment correlates best
with the burden of neurofibrillary tangles [947]. The
key interactions of apolipoprotein E and A␤ pathology
were reviewed [948].
The inhibition and reversion of A␤ misfolding and
aggregation is an approach, which has been followed
up by many research groups during years. Excellent
reviews dealing with this subject were published (in
chronological order) 1996: [949], 1998: [950, 951],
1999: [952–956], 2001: [957], 2002: [958–960], 2005:
[961, 962], 2006: [963], 2007: [964, 965], 2009: [495,
966–968], 2010: [969–971], 2011: [972, 973], 2012:
[974–976].
Tafamidis (PF-06291826, Fx-1006, Vyndaquel,
Pfizer following its acquisition of FoldRx Pharmaceuticals under license from the Scripps Research
Institute) (Fig. 12) is small-molecule transthyretin stabilizer for the oral treatment of transthyretin familial
amyloid polyneuropathy [977–980]. The drug was
approved by EMA in November 2011 was launched
in Europe in March 2012 [1724]. In June 2012, the
FDA issued a complete response letter and requested
the completion of a second efficacy study. For the identification of A␤ binding sites on transthyretin see [981];
31
for transthyretin amyloidosis see [982, 983] (Thomson
Reuters Pharma, update of September 25, 2012).
Eprodisate (1,3-propanedisulfonate disodium salt;
NC-503, Fibrillex, Kiacta; Celtic Therapeutics, St.
Thomas VI under license from Bellus Health) (Fig. 12)
is an orally active sulfated glycosaminoglycan mimetic
designed to inhibit the formation and deposition of
amyloid fibrils. A Phase III study was initiated in
December 2010 for the treatment of renal disease in
patients with AA amyloidosis [984–987] (Thomson
Reuters Pharma, update of September 5, 2012).
For ARC-029 (Archer Pharmaceuticals, Roskamp
Institute, Sarasota, FL; Phase III clinical trials),
see Chapter 7, Drugs interacting with Ion Channels
(=
/ Receptors).
For Davunetide (intranasal of via i.v. or s.c administration; Allon Therapeutics, Vancouver, Phase III
clinical trials), see Chapter 15, Peptides.
For APH-0703 (Aphios Corp., Woburn MA), a
nanoparticle formulation of APPH-9601 in Phase II
clinical trials since May 2010 (Thomson Reuters
Pharma, update of July 5, 2012), see Part 2, Chapter
2.35, Drugs interacting with Protein Kinase C.
Doxycycline hyclate (Fondazione IRCCS Policlinico San Matteo, Pavia, Italy) is in a Phase II study
(NCT01171859) in patients with transthyretin amyloidosis (n = 40) since July 2010. At oral doses of
200 mg for three months, doxycycline produced a
significantly lower decline in the ADAScog scores in
101 mild-to-moderate AD patients [988] (Thomson
Reuters Pharma, update of April 27, 2012).
ELND-005 (AZD-103; scyllo-inositol; scyllocyclohexanehexol, Elan, Dublin, Ireland, and Ellipsis
Neurotherapeutics, formerly Transition Therapeutics,
Toronto, Canada) (Fig. 12) is an orally available
inhibitor of A␤ peptide aggregation. Results of a Phase
II dose-ranging, randomized, placebo-controlled study
in 351 patients with mild-to-moderate AD treated for
78 weeks with either 250, 1,000, or 2,000 mg/day were
reported. Patients with mild AD receiving 250 mg of
ELND-005 had higher scores on the Neuropsychological Test Battery compared with placebo, which
were significant. In contrast ADCS-ADL scores were
not significant. The two higher doses were discontinued [989]. In August 2012, a Phase II study
was initiated in bipolar disorder patients in the US.
The study is expected to be completed in August
2014 (Thomson Reuters Pharma, update of September
14, 2012).
The endogenous brain inositols stabilized small
aggregates of A␤, which are non-toxic to NGFdifferentiated PC-12 cells and primary human neuronal
32
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 12. Drugs interacting with amyloid-␤.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
cultures [990]. In particular scyllo-inositol, when
given orally to transgenic mice, reversed AD phenotype, improved impaired cognition, and altered
cerebral A␤ pathology [991, 992]. Scyllo-inositol
dose-dependently rescued long-term potentiation in
mouse hippocampus from the inhibitory effects of soluble oligomers of cell-derived human A␤ [993, 994].
Elevated scyllo-inositol concentrations were found in
patients with AD [995].
Syntheses of scyllo-inositol derivatives have been
reported [996]. The synthesis of the PET ligand [18 F]1-deoxy-1-fluoro-scyllo-inositol was described [997].
A comparison of three amyloid assembly inhibitors,
scyllo inositol, epigallocatechin gallate and the molecular tweezer CLR01 (vide infra) was published
[998].
SOM-0226 (SOM Biotech SL, Barcelona) is a drug
for the potential treatment of transthyretin amyloidosis in Phase II clinical development (Thomson Reuters
Pharma, update of May 30, 2012). The structure was
not communicated.
For AAD-2004 (GNT Pharma, Suwon, South
Korea) in Phase I clinical trials (Thomson Reuters
Pharma, update of May 4, 2012). See Part 2, Chapter 2.34. Drugs interacting with Prostaglandin D & E
Synthases, Part 2, Fig. 22.
Beta amyloid modulator (Medipost, Seoul) is in
Phase I clinical trials in South Korea since September 2011 for the potential treatment of AD (Thomson
Reuters Pharma, update of May 7, 2012). The structure
was not communicated.
BLU-8499 (formerly NRM-8499; Bellus Health,
formerly Neurochem, Quebec) is a prodrug of
tramiprosate (vide infra). It was evaluated in a singlecenter, randomized, double-blind, placebo-controlled
Phase I study in 84 young and elderly healthy subjects
to assess safety, tolerability and pharmacokinetics,
which started in March 2010. The data were reported
in January 2011. It showed improved gastrointestinal tolerability and lower inter-individual variability
of drug exposure compared to comparable doses of
tramiposate (Thomson Reuters Pharma, update of
September 5, 2012).
DWP-09031 (presumed to be DWJ-301; Daewong
Pharmaceutical Co. in collaboration with Medifron,
both South Korea) inhibited the production and aggregation of A␤. By January 2012, the Korean FDA
had approved an IND for a Phase I trial. The
randomized, double-blind, placebo-controlled study
(NCT01522586) is planned in healthy male volunteers (n = 64) to assess the safety, pharmacokinetics and
pharmacodynamics of DWP-09031 (Thomson Reuters
33
Pharma, update of July 27, 2012). The structure was
not disclosed.
For Exebryl-1 (ProteoTech, Kirkland, WA and
China licensee Tasly Pharmaceuticals; in Phase I clinical trials), see Chapter 13, Natural Products.
For NP-61 (NP-0361; Noscira, previously Neuropharma, Madrid; Phase I clinical trials; Thomson
Reuters Pharma, update of May 10, 2012), see Part
2, Chapter 2.1.1.2., Dual acetylcholinesterase and A␤
inhibitors.
Systebryl (ProteoTech, Kirkland, WA) is the lead
of a series of small molecules including PTI-19 and
PTI-51 for the potential treatment of systemic AA amyloidosis. In December 2011, Systebryl was in Phase I
studies (Thomson Reuters Pharma, update of December 21, 2011). Structures were not communicated.
There are many A␤ aggregation inhibitors in preclinical evaluation (in alphabetical order):
Alzheimer’s disease therapeutics (BioChromix
Pharma AB, Solna, Sweden) are compounds, which
achieved a significant reduction in plaque load and
neurotoxic A␤ aggregates. (Thomson Reuters Pharma,
update of August 24, 2012). The structures were not
communicated.
A␤ oligomer cellular prion protein binding
inhibitors (AstraZeneca under a sublicense from Axerion Therapeutics under license from Yale University)
are interacting with the cellular prion protein, the
high affinity receptor for A␤ oligomers [999–1003]
(Thomson Reuters Pharma, update of August 17,
2012). No structures were disclosed.
A␤ protein inhibitors (Neuropore Therapies, San
Diego CA) are peptidomimetic compounds that interfere with A␤ aggregates (Thomson Reuters Pharma,
update of July 16, 2012). Structures were not communicated.
A␤/tau protein aggregation inhibitors (CNRS,
FIST SA, Paris, France) are investigated for the potential treatment of AD (Thomson Reuters Pharma, update
of August 24, 2012). Structures were not communicated.
Amyloid-derived diffusible ligands are investigated by Merz Frankfurt, Germany under license from
Acumen Pharmaceuticals (Thomson Reuters Pharma,
update of June 12, 2012). The structures of the compounds were not communicated.
ARN-4261 (New York University and Aria Neurosciences, Hamden CT) (Fig. 12) and ARN-2966
(Fig. 12) are inhibitors of A␤ aggregation. ARN-2966
reduced A␤ deposition and memory deficit in transgenic mice. Following treatment a significant 25%
reduction in A␤ plaque load was noted compared with
34
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
mice that received a vehicle control. The data demonstrated that ARN-2966 was biostable and well tolerated
in transgenic mice with blood-brain barrier penetration after both oral and intravenous dosing (Thomson
Reuters Pharma, update of August 28, 2012).
AVCRI-104P4 (University of Barcelona) (Fig. 12)
inhibited A␤ aggregation including acetylcholinesterase- and self-induced-A␤ aggregation, ␤-secretase,
acetylcholinesterase, and butyrylcholinesterase (Thomson Reuters Pharma, update of September 28, 2012).
AVN-457, AVN-458 and AVN-492 (Avineuro Pharmaceuticals, San Francisco) are nootropic agents for
the potential treatment of cognitive disorders (Thomson Reuters Pharma, update of October 22, 2012). The
structures were not disclosed.
AZP-2006 (AlzProtect, Loos, France in collaboration with INSERM and the University of Lille II) is an
A␤PP modulator of undisclosed structure (Thomson
Reuters Pharma, update of July 4, 2012).
Beta-amyloid aggregation inhibitors (Medisyn
Technologies, Minnetonka, MN / Mount Sinai School
of Medicine) demonstrated significant A␤-lowering
and anti-aggregation activity in vitro. Two compounds
also reduced the amount of A␤ in mouse brain in vivo
(Thomson Reuters Pharma, update of June 21, 2012).
Structures were not communicated.
Beta-amyloid/alpha-synuclein/tau aggregation
inhibitors (Snowdon Inc., Vancouver) are expected
to enter Phase I trials in 2012 (Thomson Reuters
Pharma, update of August 19, 2011). The structures
of the compounds were not communicated.
Beta amyloid beta sheet formation inhibitors (AC
Immune, Lausanne, Switzerland) are small molecules,
which inhibited the aggregation of A␤ to oligomeric
and fibrillar species for the potential treatment of AD
and glaucoma [1004]. Two 3-aminopyrazole moieties
carrying additional aryl substituents were connected
via a linker. The concept of 3-aminopyrazoles with a
donor-acceptor-donor hydrogen bond pattern complimentary to that of the ␤-sheet of A␤42 was first investigated by Schrader and colleagues [1005–1013] (Thomson Reuters Pharma, update of September 24, 2012).
Beta-amyloid inhibitor (Icogenex, Seattle, WA) is
a small molecule therapeutic that normalizes the production of A␤ (Thomson Reuters Pharma, update of
June 26, 2012). The structure was not disclosed.
Beta-amyloid inhibitor (Star Scientific, Glen Allen
VI through its subsidiary Rock Creek Pharmaceuticals
in collaboration with the Roskamp Institute) reduced
A␤ when applied to cells (Thomson Reuters Pharma,
update of January 3, 2012). The structure was not
disclosed.
Beta-amyloid modulators (Crossbeta Biosciences,
Utrecht, The Netherlands) are small molecules, which
target A␤ oligomers and misfolded proteins (Thomson
Reuters Pharma, update of August 24, 2012). Structures were not communicated.
Beta-amyloid precursor protein modulators
(Alzcor Pharmaceuticals, Arlington, MA) are investigated for the potential treatment of AD (Thomson
Reuters Pharma, update of July 27, 2011). Structures
were not disclosed.
BMS-869780 (Bristol-Myers Squibb) (Fig. 12)
reduced A␤42 levels in transgenic mice at oral doses
and displayed an IC50 value at A␤42 in the low
nM range. It was not hepatotoxic (Thomson Reuters
Pharma, update of August 6, 2012).
BTA-EG4 (Johns Hopkins University and Georgetown University) is a benzothiazole aniline derivative
and amyloid-␤ synthesis inhibitor for the potential
treatment of Alzheimer’s disease (Thomson Reuters
Pharma, update of October 30, 2012). The structure
was not communicated.
C36 (Medisyn Technologies, Minnetonka, MN
in collaboration with the Mount Sinai School of
Medicine) is an A␤40 and A␤42 lowering small
molecule for the potential treatment of AD (Thomson
Reuters Pharma, update of December 6, 2011). The
structure was not disclosed.
Caprospinol (SP-233; Samaritan Pharmaceuticals,
Las Vegas, NV under license from Georgetown University) (Fig. 12), a spirostenol drug, blocked the
oligomerization of A␤42 exerting a direct effect
on mitochondria [1014–1017] (Thomson Reuters
Pharma, update of March 18, 2011).
Carvedilol is a launched unselective ␣1 , ␤1 and ␤2
blocker, which inhibited A␤ fibril formation [1018].
CLR01 (University of Duisburg-Essen, Rensselaer
Polytechnic Institute, NY and UCLA) (Fig. 12) is a
molecular tweezer, which binds to lysine residues with
micromolar affinity and interferes with a combination
of hydrophobic and electrostatic interactions that are
important in the self-assembly of most amyloidogenic
proteins including A␤, tau, and ␣-synuclein [1007,
1018–1024].
CLR-097(Clera Inc., Toronto) inhibited the process
of A␤ plaque formation (Thomson Reuters Pharma,
update of December 5, 2011). The structure was not
disclosed.
Cotinine, a natural metabolite of nicotine, may be a
potential new therapeutic agent against AD [1025]. It
reduced amyloid-␤ aggregation and improved memory
in Alzheimer’s disease mice [1725].
Daunomycin inhibited A␤ fibril formation [1018].
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
DBT-1339 (Medifron, Seoul and licensee Daewoong, South Korea) (Fig. 12) is the lead compound
from A␤ protein deposition inhibitors (Thomson
Reuters Pharma, update of June 1, 2012).
Enoxaparin (Enox, a low molecular weight heparin) lowered brain A␤ load in a mouse model of AD
[1026]. It also improved cognition in APPSWE /PS1dE9
mice [1027, 1028].
GAG/carbohydrate compounds (ProteoTech,
Kirkland, WA) are glycosaminoglycan modulators
for the potential treatment of AD (Thomson Reuters
Pharma, update of June 7, 2012). Structures were not
disclosed.
Galantamine inhibited A␤ aggregation and cytotoxicity [1029].
haw-AD-14 (Hawthorn, Madison, Mississippi
under license from CoPlex) is an A␤ synthesis and tau
phosphorylation inhibitor (Thomson Reuters Pharma,
update of September 26, 2011). The structure was not
communicated.
HO-4160 (University of California at Davis)
(Fig. 12) is a spin-labeled fluorene compound that
specifically disrupted A␤ oligomers [1030].
Imipramine in part through inhibition of TNF-␣
prevented cognitive decline and A␤ accumulation in a
mouse model of AD [1031].
IPS-04001, IPS-04001 and IPS-04003 (InnoPharmaScreen, South Korea) is a specific inhibitor
of A␤ peptide and VEGF-165 interaction. By
June 2012, in vivo efficacy studies had shown a
significantly enhanced effect on the memory of
NSE-PS2/N141Ltransgenic mice (Thomson Reuters
Pharma, update of July 16, 2012). The structure were
not communicated.
KMS-88 series (Hanmi Pharmaceutical, South
Korea, the Korea Institute of Science and Technology
and Seoul National University) (Fig. 12) is a series of
aminostyryl-benzofuran derivatives inhibiting A␤ fibril formation [1032, 1033] (Thomson Reuters Pharma,
update of September 12, 2012).
Minocycline is a second generation tetracycline
that can effectively cross the blood-brain barrier.
It improved cognitive impairment in AD models
[1034]. It provided protection against A␤25-35 induced
alterations of the somatostatin signaling pathway
[1035, 1036]. It reduced microglial activation [1037,
1038]) and A␤ derived neuroinflammation [1039]. It
recovered MTT-formazan exocytosis impaired by A␤
[1040]. It reduced the development of abnormal tau
species in models of AD [1041–1043]. Minocycline
protected PC12 cells against NMDA-induced injury
via inhibiting 5-lipoxygenase activation [1044, 1045].
35
Minocycline improved negative symptoms in patients
with early schizophrenia [1046]. See also Part 2, Chapter 2.25. Drugs interacting with 5-Lipoxygenase.
NPT-4003 (Neuropore Therapies, San Diego CA) is
the lead of heterocyclic compounds that interfere with
amyloid-␤ aggregates. Detailed data were presented
at the ICAD Vancouver in July 2012 [1726]. (Thomson Reuters Pharma, update of July 16, 2012). The
structure was not communicated.
Rifampicin inhibited A␤ aggregation and neurotoxicity [1047–1049]. In a clinical trial in 101
mild-to-moderate AD patients, statistically significant
improvements in the ADAScog scores after treatment
with 300 mg rifampicin for three months were found
[988]. Rifampicin and caffeine caused an upregulation of LRP1 [1050]. The brain efflux index of A␤
in rifampicin and caffeine treated mice was significantly higher (82% and 80%, respectively) than the
brain efflux index of control mice (62%). It appears
that a yet to be identified transporter/receptor plays a
significant role in A␤ clearance, which is upregulated
by rifampicin and caffeine.
Rolitetracycline is effective as inhibitor of A␤ fibril
formation [1018].
SD-1002 (Synaptic Dynamics, Farmington CT) is a
lysosomal modulator that reduced protein deposition
of amyloid-␤1-42 oligomers for the potential treatment
of Alzheimer’s disease (Thomson Reuters Pharma,
updates of October 22, 2012). The structure was not
communicated.
SEN-1500 (Senexis, Cambridge, UK) (Fig. 12) and
follow-up compound SEN-1576 (structure not disclosed) are small molecule A␤ aggregation inhibitors
[1727] (Thomson Reuters Pharma, updates of March
23 and August 2, 2012, respectively).
Small molecule A␤ modulators (Asceneuron, a
spun-out of Merck Serono, Geneva, Switzerland) are
drugs for the potential treatment of AD (Thomson
Reuters Pharma, update of October 3, 2012). Structures
were not disclosed.
SP-08 (Samaritan Pharmaceuticals, Las Vegas, NV
under license from Georgetown University) (Fig. 12)
is an A␤ antagonist with neuroprotectant properties
(Thomson Reuters Pharma, update of March 18, 2011).
TAK-070 (University of Tokyo under license from
Takeda) is a ␤-secretase and A␤ aggregation inhibitor
(Thomson Reuters Pharma, update of July 10, 2012).
The structure was not communicated.
Tetracycline(s) showed anti-amyloidogenic activity in vitro [1051] and protected Caenorhabditis
elegans from A␤-induced toxicity by targeting
oligomers [1052].
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
For VP-20629 (Indole-3-propionic acid; OX1; INOX1; OXIGON, ViroPharma, Exton PA, under license
from Intellect Neurosciences under license from New
York University and Mindset BioPharmaceuticals;
Thomson Reuters Pharma, update of August 10, 2012),
see Chapter 11. Antioxidants.
AGT-160 (ArmaGen Technologies, Santa Monica, CA) is a recombinant IgG fusion protein
formed by the fusion of a single chain Fv antibody against A␤ plaque formation to the company’s
human insulin receptor-targeting monoclonal antibody Trojan horse for transport across the blood-brain
barrier for the potential detection and treatment of
AD (Thomson Reuters Pharma, update of January
23, 2012). See also Part 1. Chapter 1.16. Insulin
receptors.
EDN-OL1 (Edunn Biotechnology, St. Louis, Missouri under license from St. Louis University) is an
antisense oligonucleotide targeting A␤ production,
which improved memory and learning in three different AD mouse models. By February 2012, EDN-OL1
had demonstrated activity in patients with Down syndrome (Thomson Reuters Pharma, update of August
24, 2012).
NPT-001 (NeuroPhage Pharmaceuticals, Cambridge, MA) is a filamentous M13 bacteriophage that
disrupted plaque aggregation through binding of A␤.
Direct binding of M13 bacteriophage to fibrils of
aggregated A␤ was observed with high affinity of
4 nM. In an AD mouse model, A␤ plaques were
reduced by 70% after a single intracranial administration (Thomson Reuters Pharma, update of July 16,
2012).
Spheron-based therapeutics (Nymox Pharmaceutical Corp., Quebec) are compounds capable of
blocking the transformation of human spherons into
plaques [1053, 1054] (Thomson Reuters Pharma,
update of February 22, 2012).
A␤-aggregation inhibitor research programs were
ongoing at Elan [1055], at GrenPharma [1056], at GSK
[1057, 1058], at Johnson & Johnson [1059], at Pfizer
[1060], at Pharmacia-Farmitalia Carlo Erba [1061] and
at Scios [1062].
Excellent papers on A␤ aggregation inhibitors from
universities were presented (in chronological order)
1995: [1063], 1996: [1064], 1997: [1065, 1066], 2001:
[1067], 2002: [563, 1068], 2004: [1069, 1070], 2005:
[1071–1073], 2006: [1074–1082], 2007: [1083–1094],
2008: [745, 1043, 1095, 1096, 1097–1105] 2009:
[1106–1113], 2010: [391, 551, 980, 1114–1117], 2011:
[549, 643, 1118–1122] and 2012: [1033, 1123–1129,
1728].
Excellent papers on theoretical calculations on
A␤-aggregation inhibitors were published (in chronological order) 2006: [1130, 1131], 2008: [1066,
1132–1134], 2009: [1135–1137], 2011: [1138, 1139]
[1140, 1141], 2012: [1142–1144].
The Phase III development of tramiprosate
(3-amino-1-propanesulfonic acid, homo-taurine, NC531, Alzhemed, Cerebril; Bellus Health, former
Neurochem), an orally available glycosaminoglycan mimetic, was terminated in 2007 [1145–1151].
The compound was launched as a nutraceutical for
memory protection [1152]. Also the development of
ALS-499 and ALS-633 (Advanced Life Sciences,
in collaboration with Argonne National Laboratory), amyloid beta aggregation inhibitor (Zyentia),
amyloid oligomer specific antagonists (Treventis),
amyloid protein deposition inhibitor (ProteoTech),
AN-531 (Athena Neurosciences, now Elan Pharmaceuticals), AS-602704 (Ac-FPFFD-NH2 , Merck
Serono [1153]), beta amyloid aggregation inhibitors
(Cortex, Elan, Hybridon, Oceanix, Queens University
at Kingston and University of Wisconsin-Madison),
beta-amyloid modulators (Inflame Therapeutics,
Neuro-Hitech and Q-RNA), beta-amyloid precursor protein modulators (SIBIA Neurosciences in
collaboration with BMS), beta amyloid synthesis
inhibitors (BTG), CLR-01 (Clear Therapeutics, a
spin-off from UCLA), CT-500 (Creabilis Therapeutics), ID-1135 and ID-1567 (Bellus Health), lysosomal
modulators (Synaptic dynamics), MPI-442690 and
MPI-442691 (Myriad Genetics in collaboration with
the Mayo Clinic), NC-503 and NC-531 (Neurochem; Bellus Health), NHT-0112 (Neuro-Hitech),
NOX-A42 (Noxxon Pharma), NVP-AAM147 and
NVP-AAM155 (Novartis), phenserine-based amyloid inhibitors (Message Pharmaceuticals), PPI-368,
PPI-558 and PPI-1019 (Apan; all Praecis Pharmaceuticals [953, 957]), PTI-777 (ProteoTech),
Reumacon (Meda under license from Conpharm),
Ro-47-1816-001, Ro-65-7652-000, Ro-65-8564-001
and Ro-8815-001 (Roche), RS-1178 (BGC-20-1178;
Senexis under license from BTG under license
from Sankyo [1154]), RS-0406 (BGC-20-0406;
Senexis under license from BTG under license from
Sankyo [1155–1158]) and RS-0466 (Sankyo), RX-AD
(Rimonyx Pharmaceuticals), SAN-61 and SAN-161
(Sanomune, a subsidiary of DiaMedica), Semapimod
(CNI-1493; Cytokine PharmaSciences, CPSI, formerly Cytokine Networks), a cytokine inhibitor, which
inhibited A␤ production, plaque formation and cognitive deterioration in an animal model of AD [39, 40,
1729]), SEN-304, SEN-606, SEN-1186, SEN-1203,
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
and SEN-1329 (Senexis), SIB-1848 (SIBIA Neurosciences, now Merck and Bristol-Myers Squibb),
SKF-746532 (SmithKline Beecham, now GSK),
synthetic anti-beta sheet peptides (Mayo Foundation), THUR-24 (Thuris Corp.), transthyretin
(Research Foundation of the State University of New
York), and of VIP-SSM (University of Illinois) was
terminated.
Ligands interacting with amyloid-β
Since the discovery of the 11 C-PiB-PET ligand,
tremendous progress has been made in the development of new PET ligands. Considerable evidence
suggests that A␤ deposition precedes decline in cognition [1159, 1160]. The development of PET amyloid-␤
imaging agents was described [1730].
11 C-PiB (University Pittsburgh) (Fig. 13) had a
KD = 1.4 nM for AD frontal cortex and KD = 4.7 nM
for A␤ fibrils and did not bind to neurofibrillary tangles [1161]. The log P value is 1.2 [1162]. Patients
with AD typically showed a marked 11 C-PiB retention (with a significant 1.5 to 2-fold increase) in
cortical areas known to contain large amounts of
A␤ plaques [1163–1165]. 11 C-PiB positivity in MCI
indicated already advanced A␤ pathology [1166].
Significant correlations between 11 C-PiB retention
and CSF biomarkers were found in MCI patients
[1167]. Clinical severity of AD measured by the
Clinical Dementia Rating scale sum of boxes correlated with 11 C-PiB uptake in PET [1168]. 11 C-PiB
imaging of human immunodeficiency virus-associated
neurocognitive disorder was described [1169]. For a
direct comparison of 11 C-PiB, 18 F-Florbetapir, 18 FFlorbetaben, and 18 F-Flutemetamol, see [1170] for
a comparison between Pittsburgh Compound B and
Florbetapir see [1731]. Longitudinal imaging of AD
pathology with 11 C-PiB, 18 F-FDDNP, and 18 F-FDG
was described [1171–1173]. For the prediction of cognitive decline via PET of brain A␤ and tau, see [1174].
The clinical perspective of imaging of cerebral A␤
plaques was discussed [1175, 1205]. The correspondence between in vivo 11 C-PiB-PET and postmortem
assessment of plaques was discussed [1176]. Imaging brain amyloid in nondemented adults with Down
syndrome using Pittsburgh Compound B was reported
[1732].
Fred Van Leuven and coworkers carried out a systematic evaluation of the isomeric compounds with
the OH groups attached in 4, 5, and 7 positions. The
5-hydroxy analogue had the most favorable in vivo
pharmacokinetics in brain [1177, 1178].
18 F-Florbetapir
37
(18 F-AV-45; Amyvid; Avid
Radiopharmaceuticals, Philadelphia, PA, a subsidiary
of Eli Lilly, under license from the University of Pennsylvania) (Fig. 13) is a launched 18 F PET imaging agent
targeting A␤. It had a Ki of 2.87 nM, did not bind to
tau, and can easily be labeled with 18 F by an automated
synthesis [1179–1187]. By March 2010, more than
700 patients were enrolled in a Phase III trial presumed
to be the 18 F-AV-45-A07 study. Several clinical papers
appeared describing imaging with 18 F-Florbetapir
[1188–1195]. Correlations between 18 F-Florpetapir
and FDG images were reported [1196]. 18 F-Florpetapir
is useful to quantify brain amyloid load [1197]. For
a direct comparison of 11 C-PiB, 18 F-Florbetapir, 18 FFlorbetaben, and 18 F-Flutemetamol, see [1170]; for a
clinical comparison of 18 F-Florbetapir and 18 F-FDG
PET in patients with AD and controls, see [1198]. A
prospective cohort study was described [1199].
A longitudinal assessment of 18-month of cognitive
decline in mild cognitive impairment and Alzheimer’s
disease patients using florbetapir was communicated
[1733]. “From Alois to Amyvid” see [1734]. PET
imaging was also carried out in a murine model of
amyloid-␤ plaque deposition [1735].
FDA approved 18 F-Florpetapir as a PET imaging agent to estimate A␤ neuritic plaque density in
patients with cognitive impairment on April 6, 2012.
Lilly launched the imaging agent in June 2012. The
compound will be manufactured and distributed by
Cardinal Health [1200] (Thomson Reuters Pharma,
update of September 17, 2012).
18 F-Florbetaben (18 F-BAY 94-9172; 18 F-AV1/ZK; Piramal Healthcare, Mumbai, India from an
asset acquisition from Bayer under license from Avid
Pharmaceuticals and the University of Pennsylvania)
(Fig. 13) is the phenyl analogue of florbetapir. It has
a Ki of 2.22 nM [1181]. In November 2009, a Phase
III clinical trial in AD patients (n = 292) began to
assess safety and efficacy of florbetaben to detect
or exclude cerebral A␤. Data from clinical studies
were reported [1201–1208]. An in vitro characterization was disclosed [1736]. The one-step radiosynthesis
was described [1209], as was the radiation dosimetry
[1210]. In the NCT01138111 trial, 18 F-Florbetaben
PET imaging was studied in MCI patients. For a
direct comparison of 11 C-PiB, 18 F-Florbetapir, 18 FFlorbetaben, and 18 F-Flutemetamol, see [1170]; for
a comparison of 11 C-PiB and 18 F-Florbetaben, see
[1211]; for the impact of 18 F-Florbetaben PET imaging on confidence in early diagnosis of AD, see [1212]
(Thomson Reuters Pharma, update of September 6,
2012).
38
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 13. Radioligands for PET scans of amyloid-␤.
18 F-Flutemetamol (GE-067; GE Healthcare, Chal-
font, UK and Universities of Pittsburgh and Uppsala)
(Fig. 13) has a Ki of 0.74 nM [1181]. Results of a
Phase I study were reported [1213], as were results
of a Phase II study [1214, 1215]. In December 2009,
a Phase III trial sponsored by GE Healthcare was initiated in the US. By April 2010, Phase III trials were
also underway in Europe. In April 2012, preliminary
data from the two Phase III studies in terminally ill
patients and young healthy subjects were reported.
Data showed that the primary endpoint was met.
Patients (who underwent brain autopsy) showed concordance between 18 F-Flutemetamol PET images and
AD-associated A␤ brain pathology and healthy subjects showed concordance with the known lack of brain
A␤. The association between in vivo 18 F-Flutemetamol
PET imaging and in vivo cerebral cortical histopathology was described [1216], as was a combination of
biomarkers PET 18 F-Flutemetamol and MRI [1217].
For a direct comparison of 11 C-PiB, 18 F-Florbetapir,
18 F-Florbetaben, and 18 F-Flutemetamol, see [1170].
Binary classification of 18 F-Flutemetamol PET using
machine learning was disclosed [1218]. The pharmacokinetics of 18 F-Flutemetamol in wild-type rodents
were reported [1219] (Thomson Reuters Pharma,
update of October 3, 2012).
18 F-AZD-4694 (Navidea Biopharmaceuticals,
Dublin, Ohio, formerly Neoprobe Corporation under
license from AstraZeneca) is an i.v. PET ligand for the
potential imaging of A␤ depositions in AD in Phase
II development [1220]. In December 2011, a Phase III
program was planned to start in early 2013 (Thomson
Reuters Pharma, update of September 21, 2012). The
structure was not communicated. For syntheses of
additional 18 F-ligands of AstraZeneca see [1737].
BAY-1006578 (Bayer) is in Phase I clinical trials in
Finland and Sweden since June 2010 (n = 36). By October 2011, the trial was completed (Thomson Reuters
Pharma, update of April 30, 2012). The structure was
not communicated. A potential follow up compound is
BAY-1008472 [1221].
123 I-MNI-168 (Institute for Neurodegenerative
Disorders, IND, New Haven, CT) is a SPECT ligand to detect A␤ deposition in patients with AD. A
Phase I clinical trial was initiated in the US in January
2009 (n = 34). In February 2011, the trial was terminated (Thomson Reuters Pharma, update of February
10, 2012). The structure was not communicated.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
18 F-MNI-558
(Molecular NeuroImaging in collaboration with the Institute for Neuro-degenerative
Disorders, IND, New Haven, CT) is a PET agent that
binds A␤. The compound was in a Phase 0 trial in AD
patients and in volunteers (n = 10) from October 2010
to July 2011 (Thomson Reuters Pharma, update of
April 30, 2012). The structure was not communicated.
11 C-BF-227 (Fig. 14) was used for amyloid PET
imaging [1222–1225], for PET imaging of ␣-synuclein
deposition [1226, 1227], and for in vivo detection of
prion amyloid plaques [1228].
123 I-DRM-106 (Fujifilm Pharma) (Fig. 14) is
a radioiodinated imidazopyridine derivative for the
potential use as SPECT imaging agent for A␤ for the
diagnosis of AD (Thomson Reuters Pharma, update of
September 21, 2011).
18 F-Hexethal (Pfizer, under license from the University of Aberdeen), a barbiturate derivative, is an A␤
imaging agent (Thomson Reuters Pharma, update of
September 24, 2012).
11 C-SB-13 (Fig. 14) was evaluated first in postmortem brain tissues [1229] and in AD patients [1230].
18 F-Florbetapir dimer (Avid Radiopharmaceuticals, Philadelphia, PA, Eli Lilly) is a PET imaging
agent for the potential diagnosis of cerebral amyloid
angiopathy [1231] (Thomson Reuters Pharma, update
of May 8, 2012).
Dicyanovinylnaphtalenes were described for neuroimaging of A␤ [1232]. Also 18 F-labeled benzoxazoles [1233] and 18 F-labeled 2-pyridinylbenzoxazoles
and 2-pyridinylbenzothiazoles were presented for PET
imaging of A␤ plaques [1234].
The development of 11 C-AZD-2184 and 11 CAZD-2995 (both AstraZeneca [1235–1237, 1738])
and 18 F-FDDNP (Siemens Medical Solutions Molecular Imaging and UCLA) (Fig. 14) was terminated.
18 F-FDDNP was the first PET tracer used in vivo for
detection of cerebral A␤ plaques in 2002 [1238]. 18 FFDDNP binds to A␤ and neurofibrillary tangles in AD,
to prion plaques in Creutzfeldt-Jakob disease, to A␤
deposits in cerebral amyloid angiopathy, and to Lewy
bodies in PD and DLB [1161]. It was used for measuring amyloid-␤ and tau levels in adults with Down’s
syndrome [1739]. The ligand is still used for prediction of cognitive decline [1174, 1740]. Longitudinal
imaging of AD pathology using 11 C-PiB, 18 F-FDDNP,
and 18 F-FDG PET was described [1239]. 18 F-FDDNP
PET allowed a prediction of cognitive decline based
on hemispheric cortical surface maps [1240].
123 I-IMPY (Avid Radiopharmaceuticals, Philadelphia, PA, under license from University of Pennsylvania, Fig. 14) is a SPECT ligand for imaging studies
39
[1241, 1242]. Its Ki is 15 nM [1243]. The safety and
biodistribution was evaluated [1244]. The signal-tonoise ratio for plaque labeling is not as robust as that
of 11 C-PiB. 11 C-PiB showed a S/N ratio of about 2.5,
while 123 I-IMPY displayed a ratio of 1.8–2.0, between
30 and 50 min after an i.v. injection [1181]. Its development was terminated.
The development of amyloid binding PET
ligands (Aventis), fluoropegylated indolyl-phenylacetylenes (Avid Radio-pharmaceuticals), 11 C-6-MeBTA (University of Pittsburgh), and of 18 F-SMIBRW372 (Siemens Medical Solutions Molecular Imaging) was terminated.
Inhibitor of serum amyloid P component binding
The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of A␤ deposits
and contributes to the pathogenesis of amyloidosis
[1245–1247].
Ro-63-8695 (CPHPC; Pentraxin Therapeutics, London under license from Roche) (Fig. 14) is a
competitive inhibitor of serum amyloid P component
binding to amyloid fibrils (IC50 = 0.9 ␮M). First results
from in vivo mouse and human studies have been communicated [1245, 1248–1250]. In addition, Pentraxin
Therapeutics and GSK are investigating a combination
of CPHPC with a humanized antibody for the potential
treatment of amyloidosis (Thomson Reuters Pharma,
update of March 22, 2012).
Vaccines against amyloid-β
AN-1792 (AIP-001; Elan and American Home
Products, later Wyeth, now Pfizer) was the first vaccine against AD in clinical trials. The antigen was
synthetic A␤42 , which was administered with QS-21
from the Stimulon family of saponins purified from the
bark of Quillaja saponaria as adjuvant [1251, 1252].
The multicenter double-blind Phase IIa study in the
US and Europe involving 375 patients with mild-tomoderate AD started in the third quarter of 2001.
Treatment of patients with AN-1792 plus adjuvant
and the adjuvant alone as placebo was in a ratio of
4 : 1. 18 patients developed meningoencephalitis probably due to an inappropriate T cell activation and/or
the proinflammatory Th1 type of adjuvant. The study
was discontinued in March 2002 [1253]. Nevertheless, many important data could be collected. From
129 patients immunized with the drug, 25 were classified as antibody responders after 4.5 years. These
patients showed significantly slower decline on the
40
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 14. PET and SPECT ligands.
disability assessment for dementia and a significant
difference on a dependence scale compared to placebotreated patients. Antibody responders also showed less
of a decline in a memory test. The scientific harvest
of this single clinical trial is listed in chronological
order [1254–1286] (Thomson Reuters Pharma, update
of August 24, 2012).
Affitope AD-02 (Affiris, Vienna AT and licensee
GlaxoSmithKline Biologicals) is a six amino acid peptide vaccine targeting the N-terminus of A␤ only, when
it is free. The adjuvant is aluminum hydroxide. The
antibody response is focused exclusively on A␤ and
did not show crossreactivity to A␤PP [1287, 1288]. A
European Phase II clinical trial in 420 patients in Austria, Germany, France, the Czech Republic, Slovakia,
and Croatia started in April 2010 (Thomson Reuters
Pharma, update of August 1, 2012).
CAD-106 (Cytos Biotechnology, Zurich and Novartis) is an A␤1-6 peptide linked to a Q␤ virus-like
particle for the s.c. treatment of patients with AD.
One Phase IIa trial was initiated in July 2008 (n = 27),
and a second Phase IIa trial was started in October
2008 (n = 30). The safety, tolerability, and antibody
response of active A␤ immunotherapy with CAD106 in patients with AD was published [1289]. For
comments, see [1290, 1291]. It was found that 80%
of the patients involved in the trial developed their
own protective antibodies against A␤ without suffering any side-effects over the three years of the study.
The researchers believe that the CAD106 vaccine is a
tolerable treatment for patients with mild-to-moderate
AD. In March 2010, a randomized, placebo-controlled,
multicenter, Phase II trial began in patients (n = 120)
in the US, Canada, and Europe with mild AD [1276,
1292, 1293]. Preclinical results in transgenic mice were
presented [1294] (Thomson Reuters Pharma, update of
July 26, 2012).
Vanutide cridificar (ACC-001, PF-05236806;
Janssen Alzheimer Immunotherapy, Dublin, Ireland acquiring Elan’s Alzheimer’s Immunotherapy
Program and Pfizer) is a peptide fragment of A␤ conjugated to the mutated diphtheria toxin protein CRM197.
The adjuvant is QS-21. In May 2007, a randomized,
multicenter, double-blind, placebo-controlled, parallel
assignment, safety/tolerability/immunogenicity Phase
II trial in patients with mild-to-moderate AD (n = 56)
began [1295]. In July 2009, Pfizer began a multicenter, randomized, unblinded, QS-21-adjuvanted,
long-term, Phase II trial of vanutide cridificar (3, 10,
and 30 microg, im) in patients (n = 160) in the US.
At that time the estimated study completion date was
September 2014. In August 2009, an additional study
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
was initiated in Japanese subjects (n = 32) [1276]
(Thomson Reuters Pharma, update of August 13,
2012).
ACI-24 (AC Immune, Lausanne, Switzerland) is an
A␤1-15 peptide to which on both ends two lysines
were attached, which are tetrapalmitoylated on the
␧-nitrogens. The antigen is embedded in a liposome membrane. Adjuvant is a mixture of the lipids
DMPC, DMPG, cholesterol, and MPLA in a ratio
of 9 : 1 : 7 : 0.06, respectively [1296, 1297]. The drug
restored memory defects of transgenic AD mice.
The IgF subclasses of the antibodies generated from
the vaccine were mostly IgG2b indicating a noninflammatory Th2 isotype. CD and NMR revealed
predominantly ␤-sheet conformation. The drug is
currently evaluated in a Phase I/II clinical trial in
Denmark, Finland, and Sweden (Thomson Reuters
Pharma, update of June 19, 2012).
Affitope-AD-03 (Affiris, Vienna, Austria and
licensee GlaxoSmithKline Biologicals) entered a
Phase I clinical trial in October 2010. In November 2011, the study was completed (Thomson Reuters
Pharma, update of April 4, 2012).
UB-311 (United Biomedical, Hauppauge, NY) is
an intramuscularly administered vaccine targeting Nterminal amino acids 1-14 of A␤ in Phase I clinical
trials in Taiwan in patients with mild-to-moderate AD
(n = 18) [1298] (Thomson Reuters Pharma, update of
June 25, 2012).
V-950 (Merck, Whitehouse Station, NJ) is an
N-terminal A␤ peptide conjugated to an aluminumcontaining adjuvant with or without ISCOMATRIX
(an adjuvant containing saponin, cholesterol, and
phospholipids) [1299]. Mild-to-moderate AD patients
(n = 124) received six injections/year of increasing
doses of either placebo or V-950 in the presence or
absence of varying concentrations of ISCOMATRIX
in Phase I clinical trials in the US and Sweden over
a four year period [1276] (Thomson Reuters Pharma,
update of February 24, 2012).
There are numerous vaccine preparations in preclinical evaluation (in alphabetical order):
ABvac40 and ABvac42 (Araclon Biotech,
Zaragoza, Spain) are active therapeutic antibody
vaccines awaiting approval for clinical trials [1741]
(Thomson Reuters Pharma, update of June 25, 2012).
ADepVac (Ichor Medical Systems, San Diego, CA
in collaboration with the University of California at
Irvine and the Institute for Molecular Medicine) is a
DNA vaccine using the TriGrid electroporation technology [1300] (Thomson Reuters Pharma, update of
July 13, 2012).
41
ALZ-101 (Alzinova, Goteborg, Sweden, a spin-off
of MIVAC Development) is a specific oligomerdirected therapeutic vaccine (Thomson Reuters
Pharma, update of July 18, 2012).
ALZ-301 (Alzinova, Goteborg, Sweden, a spin-off
of MIVAC Development) is an A␤40 oligomer targeted replacement therapy (Thomson Reuters Pharma,
update of July 18, 2012).
Alzheimer’s disease vaccine (VLP Biotech, San
Diego CA) is a vaccine that activates antibodies against
A␤ protein (Thomson Reuters Pharma, update of May
3, 2012).
Amyloid-␤ 3-10 DNA vaccination (China Medical University, Shenyang) suggested a potential new
treatment for AD [1301–1305].
Active immunization with Ankyrin G, a neuronal
cytoskeletal protein, with Freund’s adjuvant complete
of arcA␤ mice reduced A␤ pathology [1306].
BAN-2203 (BioArctic Neuroscience, Stockholm,
Sweden) is an immunotherapeutic vaccine targeting
A␤ protofibrils (Thomson Reuters Pharma, update of
January 7, 2011).
BBS-1 BACE inhibitor mAb vaccine (Nasvax,
Ness Ziona, IL under license from Ramot at Tel Aviv
University) is based on a lead mAb candidate blocking
␤-site-1, which inhibited the ability of BACE to cleave
A␤PP (Thomson Reuters Pharma, update of July 30,
2012).
C12 (Pharma Bio, Moscow, Russia) is a program
of therapeutic vaccines comprised of synthetic peptide
fragments of the ␣7 nicotinic acetylcholine receptor
used to generate antibodies that block A␤ binding to
neurons (Thomson Reuters Pharma, update of March
29, 2012).
EB-101 (Atlas Pharmaceuticals, Sunnyvale, CA)
is a synthetic human A␤42 /sphingosine-1-phosphate/
liposome vaccine (Thomson Reuters Pharma, update
of July 27, 2012).
A T cell-based vaccination with Glatimer acetate
of AD double-transgenic (A␤PP/PS1) mice resulted
in decreased plaque formation and induction of
neurogenesis. Dendritic-like (CD11c) cells produced
insulin-like growth factor 1 [1307].
MER-5101 (Mercia Pharma, Scarsdale, NY) is a
vaccine comprised of an A␤ peptide conjugate coupled
to an immunogenic carrier protein and the company’s Th2-biased adjuvant MAS-1 (Thomson Reuters
Pharma, update of January 27, 2012).
Mimovax (MV-01; Affiris, Vienna AT) is an
AFFITOPE-based vaccine targeting truncated and
modified forms of A␤ (Thomson Reuters Pharma,
update of April 2, 2012).
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W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
NU-700 (Nuron Biotech, Exton, PA under license
from Vitruvian BioMedical under license from the
University of Texas Southwestern Medical Center) is
an adjuvant free, gene-base (DNA) A␤42 vaccine for
the potential treatment or prevention of AD (Thomson
Reuters Pharma, update of May 22, 2012).
Recombinant adenovirus vector vaccine (Vaxin,
Birmingham, AL in collaboration with AnC Bio,
South Korea) elicited an immune response against A␤
using Crucell’s PER.C6 technology for the potential
intranasal treatment of AD (Thomson Reuters Pharma,
update of May 2, 2012).
RV-03 (Intellect Neurosciences, New York, NY) is
a peptide vaccine developed using the RECALL-VAX
technology targeting both A␤ and a truncated delta tau
protein (Thomson Reuters Pharma, update of August
21, 2012).
SeV-amyloid beta RNA vaccine (DNAVEC,
Tsukuba, Japan) is an intranasal vaccine comprising
a Sendai virus vector encoding the A␤ gene [1308]
(Thomson Reuters Pharma, update of September 21,
2011).
Excellent papers on A␤ vaccines from universities
were presented (in chronological order) 2000: [1309,
1310]; 2001: [1311]; 2004: A␤1-42 gene vaccination
[1312]; 2005: a synthetic universal Th cell pan HLA
DR epitope, pan HLA DR-binding peptide (PADRE),
in which the PADRE-A␤1-15 sequence lacks the T cell
epitope of A␤ [1313]; 2006: an A␤ derivative in alum
adjuvant [1314], an intranasal dendrimeric A␤1-15 vaccine [1315–1319]; 2007: an oral vaccination using
a recombinant adeno-associated viral vector carrying A␤ cDNA (AAV/A␤) [1320], a transcutaneous
administration of aggregated A␤1-42 plus the adjuvant
cholera toxin [1321], a mannan-A␤28 conjugate [1322,
1323]; 2008: a DNA epitope vaccine that expresses epitopes of A␤42 [1324]; 2009: K6 A␤1-30-NH2 in alum
adjuvant [1325], an A␤1-33-MAP peptide to markedly
reduce intracellular A␤ deposits [1326], K6A␤1-30 for
immunizations of old primates [1327], A␤1-42 vaccinations also reducing mouse tau pathology [1328];
2010: an oral vaccination with GFP-A␤ [1329], immunization of aged beagle dogs with aggregated A␤1-42
formulated in an alum adjuvant [1330], active immunization with A␤1-42 emulsified in CFA containing
Mycobacterium tuberulosis extract [1331], lowering
of A␤ plaque burden by the SDPM1 peptide, a 20
amino acid peptide bound by cysteines that binds
tetramer forms of A␤1-40 and A␤1-42 amyloids [1332];
2011: two novel anti-A␤ vaccines consisting of virus
like particles [1333], the identification of the shortest A␤-peptide generating specific antibodies [1334];
2012: preventive immunization of aged primates
[1335].
Excellent reviews on A␤ vaccines have been provided (in chronological order) 2001: [1336], [1337],
2002: [1257, 1338–1341], 2003: [1342]), 2004:
[1343]), 2005: [1344–1346], 2006: [1347–1349],
[1350], 2007: [1351–1355], 2008: [1356–1359],
2009: [1282, 1360–1363], 2010: [1364–1370], 2011:
[1371], [1372–1374], and 2012: [23].
A clinical review of active and passive immunotherapeutic approaches in AD targeting A␤ was presented
[1375, 1376].
The development of A␤ retroparticles (University
of Heidelberg and Novartis [1377]), Abloid (Virionics), ACC-002 (Elan), AFFITOPE AD-01 (Affiris),
Alzheimer’s vaccine (Lundbeck under license from
Pharmexa), Alzheimer’s vaccine (Mindset BioPharmaceuticals), Alzheimer’s disease vaccines (University of South Florida and University of New Mexico),
anti-amyloid-␤ vaccines (Wyeth, now Pfizer and
Janssen Alzheimer Immunotherapy), DNA vaccine
(University of Texas, Southwestern Medical Center), immunotherapy vaccine (Prana Biotechnology),
KNX-Vaccine3A (Kinexis under license from the University of California at Irvine), PEVIPRO (Pevion
Biotech [1378]), PX-106 (Lundbeck/Pharmexa), and
RV-01 (Intellect Neurosciences) was terminated.
Antibodies against amyloid-β
Bapineuzumab (AAB-001; Janssen Alzheimer
Immunotherapy, Dublin, Ireland following the acquisition of Elan’s Alzheimer’s Immunotherapy Program
and Pfizer) is a humanized monoclonal antibody raised
against eight amino acids in the N-terminus of A␤ for
the potential i.v. and s.c. treatment of AD. A Phase III
clinical study started in December 2007. The Phase III
program included two trials in ApoE4-positive patients
(n = 800 in the US and EU) and two in ApoE4-negative
patients (n = 1,250 in the US and EU) for 18 months
each and three extension studies for both ApoE4 and
non-ApoE4 arms with three doses, 0.5, 1, and 2 mg/kg.
The highest dose had to be abandoned due to vasogenic
edema safety concerns. One extension study started in
July 2009 (n = 1,350), two additional extension studies
in December 2009 in the EU and Australia (n = 800 and
1,000, respectively). Clinical results from the Phase
I and Phase II studies were reported [1276, 1361,
1379–1382] as was a 11 C-PiB PET assessment [1383]
and the effects on CSF biomarkers [1384]. Reviews on
bapineuzumab were published (in chronological order)
[23, 1385–1392]. For the scientific basis see the Nature
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Medicine paper [1393]. The pharmacokinetic profile of
125 I-labeled 3D6, the mouse parent antibody of bapineuzumab, in transgenic mice was reported [1742].
In July 2012, Pfizer reported that the ’302 study in
ApoE4 carriers did not meet its primary endpoints.
Pfizer, Johnson & Johnson, and Elan announced that
development of i.v. bapineuzumab was terminated
(Thomson Reuters Pharma, update of September 18,
2012).
Solanezumab (LY-20622430; Lilly) is a middomain humanized monoclonal antibody selective for
soluble A␤. Three Phase III studies were initiated
in patients with mild-to-moderate AD (n = 1,000) in
May 2009, patients received 400 mg of solanezumab
or placebo i.v. every 4 weeks for 80 weeks.
First results were disclosed (in chronological order)
[1276, 1394–1398]. Safety and biomarker effects of
solanezumab in patients with AD was communicated
[1399]. Solanezumab failed to meet the cognitive and
functional primary endpoints of two Phase III AD trials. But it showed a significant reduction in cognitive
decline in patients with mild AD. The open-label
EXPEDITION-EXT extension trial, which is fully
enrolled, will continue as planned (Thomson Reuters
Pharma, update of September 7, 2012).
Gantenerumab (R-1450; Roche under license from
MorphoSys) is a human anti-A␤ monoclonal antibody. A Phase II clinical trial in Canada (n = 360)
was initiated in January 2011. Prodromal AD patients
(NCT01224106) are to receive 105 or 225 mg administered by s.c. injection every 4 weeks for 104 weeks to
evaluate effects on cognition and functioning, safety,
and pharmacokinetics. In June 2012, the trial was
expanded to a Phase II/III trial. The trial size will be
increased from 360 to 770 participants. The mechanism of A␤ removal was described [1400, 1401]. An
expert opinion was provided [1402] (Thomson Reuters
Pharma, update of September 5, 2012).
Crenezumab (MABT-5102A; RG-7412; Genentech under license from AC Immune, Lausanne,
Switzerland) is an anti-A␤ humanized monoclonal antibody as a conformation-specific, passive
immunotherapy for the potential i.v or s.c. treatment of
AD. A Phase II clinical trial (n = 372; NCT01397578)
was initiated in April 2011. The first Alzheimer’s Prevention Initiative will study the effects of crenezumab
in 300 people from a large family in Columbia with
a rare genetic mutation that typically triggers AD
symptoms around age of 45. It is a collaboration
between the National Institutes of Health (NIH), Banner’s Alzheimer’s Institute, and Genentech over five
years starting in 2013. Data and findings will be shared
43
publicly after the study completion. The scientific basis
for the selection of crenezumab was published recently
[1403] (Thomson Reuters Pharma, update of September 5, 2012).
GSK-933776A (GSK) is a monoclonal antibody
for the i.v. treatment of AD and age-related macular
degeneration. A Phase II trial (n = 162) of age-related
macular degeneration started in the US in August
2011 (Thomson Reuters Pharma, update of August 24,
2012).
The topic intravenous immunoglobulins as a treatment for AD, the rationale and current evidence was
described in reviews [1404, 1405, 1743].
Immune globulin intravenous human (IVIg;
launched as Gammagard in the US and as Kiovig
in Europe; Baxter International, Deerfield, IL) is
a highly purified solvent/detergent-treated, sterile,
freeze-dried preparation derived from human plasma
for the treatment of primary immunodeficiency disease. This pool of human immunoglobulins obtained
from healthy donors contains naturally occurring
anti-A␤ antibodies. In a Phase II trial in 24 patients,
the eight-person placebo group worsened, whereas
the 16 treated patients improved moderately on both
cognitive and quality-of-life measures over the first
6 months [1406–1408]. A Phase III clinical trial in
AD patients enrolling 390 patients was initiated in
September 2008. Trial completion is expected by the
end of 2012 (NCT00818662, NCT00299988) [1276].
The first report of long-term (three-year) stabilization
of AD symptoms with IVIG (Gammagard, Baxter),
including no decline on measures of cognition, memory, daily functioning, and mood, was reported in
July 2012 at the Alzheimer’s Association International
Conference in Vancouver. Sales in 2011 amounted to
1,541 million USD. For preclinical data, see [1409,
1410] (Thomson Reuters Pharma, update of October
3, 2012).
Octagam (Octapharma, Lachen, Switzerland) is
a 10% liquid intravenous immunoglobulin launched
for the treatment of primary immunodeficiency. By
December 2008, a double-blind, randomized, Phase
II clinical trial (NCT 00812565) in 58 patients with
AD had been initiated in the US. Clinical data were
presented at the AAIC in Paris in July 2011 (Thomson
Reuters Pharma, update of April 3, 2012).
Flebogamma DIF 10% (or 5%) (Grifols SA,
Barcelona) is a 10% (or 5%) double inactivated and
filtered immunoglobulin therapy for the treatment of
primary immunodeficiency. Data were presented on a
single-center, open-label, pilot study on the use of Flebogamma DIF 0.5 g/kg i.v., q2w for 6 months in AD
44
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
patients (n = 4) (Thomson Reuters Pharma, update of
March 23, 2012).
BAN-2401 (Eisai under license from Bioarctic
Neuroscience, Stockholm, Sweden) is a humanized
monoclonal antibody that targets the large soluble
amyloid product (protofibril A␤). A Phase I trial in 80
patients with mild-to-moderate AD began in September 2010. Eisai plans to co-administer BAN-2401 with
donepezil and memantine (Thomson Reuters Pharma,
update of July 19, 2012).
NI-101 (BIIB-037, BART; Biogen Idec, Weston,
MA under license from Neuroimmune Therapeutics,
Zurich Switzerland) is a recombinant chimeric human
IgG1 mAb targeted against A␤. A Phase I clinical trial
(n = 40) in patients with mild-to-moderate AD started
in the US in July 2011 (Thomson Reuters Pharma,
update of September 24, 2012).
PF-05236812 (AAB-003; Janssen Alzheimer Immunotherapy and Pfizer) is a humanized monoclonal
antibody targeted against A␤. In October 2010, a randomized, double-blind, placebo-controlled, adaptive,
Phase I trial was initiated in patients with mild-tomoderate AD (n = 80) in the US [1411] (Thomson
Reuters Pharma, update of August 13, 2012).
RN6G (Rinat Neuroscience Corp., New York, now
Pfizer) is an anti-A␤ antibody for the potential i.v.
treatment of age-related macular degeneration in Phase
I trial (n = 45) since April 2009 in the US. In April
2012, a randomized, double-blind, placebo-controlled,
Phase II study was planned in patients with geographic
atrophy secondary to age-related macular degeneration
(expected n = 276) to assess the safety and efficacy of
RN6G [1412] (Thomson Reuters Pharma, update of
September 11, 2012).
SAR-228810 (sanofi) is an anti-protofibrillar A␤
monoclonal antibody. A randomized, double-blind,
placebo-controlled, Phase I trial in patients with mildto-moderate AD (n = 48) was initiated in Sweden in
January 2012. The study is scheduled to complete in
December 2013 (Thomson Reuters Pharma, update of
July 27, 2012).
There are currently many antibodies for the potential treatment of AD and closely related diseases in
preclinical evaluation (in alphabetical order):
4E10 (Prana Biotechnology, Parkville, Australia) is
a monoclonal antibody targeting a proprietary pathological A␤ target epitope (Thomson Reuters Pharma,
update of November 2, 2011).
6F6 (GSK) is an anti-A␤ monoclonal antibody for
the potential treatment of age-related macular degeneration (Thomson Reuters Pharma, update of June 9,
2011).
9D5 (University of Göttingen, MBM ScienceBridge) targets pyro-Glu-A␤ peptide oligomers for the
potential diagnosis and treatment of AD [1413] (Thomson Reuters Pharma, update of August 7, 2011).
A-887755 (Abbott Laboratories) is an A␤,
oligomer-selective, mouse monoclonal antibody
generated using a homogenous, synthetic A␤20-42
oligomer peptide (Thomson Reuters Pharma, update
of February 27, 2012).
A-992401 (Abbott Laboratories) is a mAb targeting the receptor for advanced glycation-end-products
(Thomson Reuters Pharma, update of December 1,
2010).
Ab40-4-42 (Ilsung Pharmaceutical, Seoul) is a
biological therapeutic, which acted by inhibiting
A␤ aggregation and cytotoxicity (Thomson Reuters
Pharma, update of May 14, 2012).
ACU-193 (Acumen Pharmaceuticals, Livermore
CA) is a monoclonal antibody against amyloid-derived
diffusible ligands (Thomson Reuters Pharma, update
of August 16, 2012).
AD-0802 (Bioarctic Neuroscience, Stockholm,
Sweden) is a humanized mAb with affinity for binding
to A␤ protofibrils. It is a potential follow-up compound
to BAN-2401 (vide supra) (Thomson Reuters Pharma,
update of January 7, 2011).
AGT-160 (ArmaGen Technologies, Santa Monica,
CA) is a recombinant IgG fusion protein formed by the
fusion of a single chain Fv antibody against A␤ plaque
formation to the company’s human insulin receptortargeting monoclonal antibody Trojan horse for the
transport across the blood-brain barrier. A 1 mg/kg i.v.
dose of AGT-160 was administered twice a week for
12 weeks to transgenic AD mice resulting in a 40%
decrease in the brain concentration of A␤ (Thomson
Reuters Pharma, update of January 23, 2012). See also
Part 1. Chapter 1.16. Drugs interacting with the insulin
receptor.
ALZ-201 (Alzinova, Goteborg, Sweden, a spinoff of MIVAC Development) is an oligomer-specific
A␤ monoclonal antibody (Thomson Reuters Pharma,
update of July 20, 2012).
Amyloid
precursor
protein
C-terminal
fragment-targeted monoclonal antibodies (Ecole
Polytechnique Fédérale de Lausanne, EPFL) is
a monoclonal antibody targeted to the 99 amino
acid C-terminal fragment of A␤PP (A␤PP-C99)
(Thomson Reuters Pharma, update of March 31,
2011).
Anti-amyloid beta antibodies (Kyowa Hakko
Kirin under license from Immunas Pharma, OncoTherapy Science Inc.) are antibodies targeting A␤
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
oligomers (Thomson Reuters Pharma, update of
August 6, 2012).
Brain-targeted BACE1 antibody (Genentech,
Roche Holding) is a bi-specific antibody against
BACE1 and the transferrin receptor to allow transcytosis across the blood-brain barrier [1414, 1415]
(Thomson Reuters Pharma, update of May 14, 2012).
This technique was pioneered by Prof. William M.
Pardridge of UCLA [1416–1422].
CPHPC+antibody (Pentraxin, London and GSK) is
a combination of CPHPC, which lowers blood levels of
serum amyloid P component (see Chapter 16.2) and a
humanized antibody for the treatment of amyloidosis
[1249] (Thomson Reuters Pharma, update of March
22, 2012).
DLX-212 (Delenex Therapeutics, Zurich, Switzerland) is an anti-A␤ antibody fragment (Thomson
Reuters Pharma, update of March 29, 2012).
Fully human monoclonal antibodies (Intrexon,
Blacksburg VI after its acquisition of Immunologix)
are targeting A␤ plaques for the potential treatment
of AD (Thomson Reuters Pharma, update of June 13,
2012).
IN-N01 (Intellect Neurosciences under license from
Immuno-Biological Laboratories, IBL, New York,
NY) is an antibody drug conjugate consisting of a
A␤-specific humanized mAb employing its ANTISENILIN technology, for the potential treatment of
AD, glaucoma, age-related macular degeneration and
traumatic brain injury. In September 2012, Intellect
planned to conduct studies in combination with tau
mAbs TOC-1and TauC3 (Thomson Reuters Pharma,
update of September 20, 2012).
IN-N01-OX2 (Intellect Neurosciences, New York,
NY) is a humanized IgG4 monoclonal antibody conjugated to melatonin developed using its CONJUMABA technology for the potential treatment of age-related
macular degeneration and Alzheimer’s disease (Thomson Reuters Pharma, update of October 2, 2012).
Lpathomab (LT-3015; Lpath Inc., San Diego,
CA) is a systemic formulation of a humanized antilysophosphatidic acid monoclonal antibody for the
potential treatment of fibrosis, ocular inflammation,
and CNS disorders including AD [1423] (Thomson
Reuters Pharma, update of August 28, 2012).
MDT-2007 (Medronic, Minneapolis, MN) is a
humanized anti-A␤ monoclonal antibody, the humanized version of the mouse mAb 6E10 (Thomson
Reuters Pharma, update of January 6, 2012).
Nanobody therapeutics (Ablynx, Gent Belgium
and licensee Boehringer Ingelheim) are naturallyoccurring single chain antibodies of Camelidae. In
45
April 2012, a CTA was submitted to European regulatory authorities for a Phase I study (Thomson Reuters
Pharma, update of August 23, 2012).
NEOD-001 (Onclave Therapeutics, Dublin, Ireland
and Neotope Biosciences, South San Francisco, CA
and Elan) is a proprietary monoclonal antibody for
the potential treatment of AL amyloidosis. In February
2012, the drug was awarded Orphan status by the FDA
for AA amyloidosis and AL amyloidosis (Thomson
Reuters Pharma, update of June 27, 2012).
STC-103 (STC Biologics, Cambridge, MA) is a
novel Fc fusion protein therapeutic for the potential
treatment of AD (Thomson Reuters Pharma, update of
August 10, 2012).
Excellent papers on A␤ antibodies from universities
and basic research from companies were presented (in
chronological order) 1996: [1424], 1997: [1425]; 2000:
[1393]; 2005: [1426, 1427], 2006: [1428, 1429], 2007:
[1430–1441], 2008: [1442–1447], 2009: [1448–1454],
2010: [1366, 1455–1460], 2011: [1461–1465], 2012:
[1466, 1467, 1744].
Excellent reviews were provided (in chronological order) 2006: [1350], 2007: [1468–1470], 2008:
[1356, 1358, 1471, 1472], 2009: [1360, 1361,
1473–1475], 2010: [1369]; 2011: [23, 1371, 1388,
1389, 1476–1478], 2012: [1479]. The challenge
of adverse effects of immunotherapy for AD was
addressed [1480].
A clinical review of active and passive immunotherapeutic approaches in AD targeting A␤ was presented
[1375, 1376].
The development of 11A1 (a monoclonal antibody against the toxic conformer of A␤42 ; Tokyo
Metropolitan Institute of Gerontology, Kyoto University and Immuno-Biological Laboratories), A-11
(A␤ deposition-inhibiting antibody; Kinexis under
license from the University of California), AAB002 (Janssen Alzheimer Immunotherapy and Pfizer),
ABP-102 (Abiogen Pharma; a catalytic monoclonal
antibody, an abzyme), ACU-5A5, ACU-0101979
and huC091 (Acumen Pharmaceuticals), anti-Abeta
monoclonal antibodies (Mapp Biopharmaceutical in
collaboration with Johns Hopkins University), the
anti-amyloid beta antibody therapy targeting specific forms of the A␤ parenchymal plaque (sanofi under
license from Rockefeller University), anticalin (Pieris,
an antibody against residues 16-26 of A␤), AZD3102 (AstraZeneca), bapineuzumab (AAB-001;
Janssen Alzheimer Immuno-therapy and Pfizer), beta
amyloid deposition-inhibiting antibodies (amyloidosis, Kinexis), beta amyloid-targeting antibodies
(Mindset BioPharmaceuticals), encapsulated scFv-
46
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
beta 1-expressing cells targeting the EFRH tetrapeptide region of A␤ (scFv-beta 1; Novartis in collaboration with the Institute for Research in Biomedicine
and the Ecole Polytechnique Fédérale de Lausanne), ESBA-212 (ESBA Tech, Nestlé, a humanized
single-chain antibody directed against A␤), KNXMonoclonal204 and KNX-Monoclonal205 (Kinexis
under license from the University of California at
Irvine), m266 (an antibody specific for the central
domain of A␤; Lilly [1481, 1482]), and ponezumab
(PF-4360365; RN-1219; RI-1219; Rinat Neuroscience
and Pfizer) [1276, 1483–1485] a humanized monoclonal antibody specific for the C-terminus of A␤40 ,
was terminated.
DRUGS INTERACTING WITH TAU
A hallmark of the AD brain is the presence
of inclusions within neurons that are comprised of
fibrils formed from hyperphosphorylated microtubulestabilizing protein tau (paired helical filaments and
neurofibrillary tangles [1486–1489]. The formation
of misfolded multimeric tau species is believed to
contribute to the progressive neuron loss and cognitive impairments of AD [1490]. Tau suppression in
a neurodegenerative mouse model improved memory
function [1491]. The precise composition of the neurotoxic species Tau-P* is not defined yet [1486]. The
levels of early multimeric tau-aggregates that preceded
the neurofibrillary tangles were found to correlate with
memory deficits [1492]. The sites of phosphorylation and the involved kinases were compiled [1493,
1494]. The tau phosphorylation pathway genes were
described [1495]. Although A␤ plaques may play a
key role in AD pathogenesis the severity of cognitive
impairment correlated best with the burden of neurofibrillary tangles described in an exhaustive review
of the literature [1496, 956]. A␤ and tau influence each
other in the mediation of toxicity. A␤ formation in
A␤PP transgenic mice caused hyperphosphorylation
of tau, whereas there was no overt A␤ plaque pathology in tau transgenic mice. Immunization against A␤
in triple transgenic mice resulted in reduced levels
of hyperphosphorylated tau. Tau reduction prevented
A␤ induced defects in the axonal transport of mitochondria. Combination of these data led to the two
step tau axis hypothesis of AD [1497–1499]. First,
postsynaptic toxicity of A␤ is tau-dependent, because
tau interacts with FYN [1500], which is localized to
the dendritic compartment, where it phosphorylates
the NMDA receptor subunit 2B, mediates their inter-
action with the postsynaptic density protein 95, an
interaction required for A␤ toxicity and second, A␤
triggers progressively increased phosphorylation of tau
compromising the binding of tau to microtubules leading to increasing dendritic tau levels [1501]. For a
very instructive figure depicting these interactions, see
[1502]. The synaptic accumulation of hyperphosphorylated tau oligomers is associated with dysfunction of
the ubiquitin-proteasome system [1503].
A cascade of biomarkers was proposed: A␤ precedes
tau-mediated neuronal injury; A␤- and tau-mediated
abnormalities precede neuroimaging biomarkers such
as changes in hippocampal or ventricular volumetry
measured by MRI; and all of these precede cognitive change marked by progressive deterioration
in episodic memory and other cognitive domains
such as executive functions abilities [1504–1506].
In a longitudinal study in 172 participants (AD:
n = 41; MCI: n = 85; and normal controls: n = 46),
the temporal relations among the four classes of
biomarkers were examined. Results indicated that CSF
A␤ effects on cognition change were substantially
attenuated by CSF tau and measures of brain structure
and function and CSF tau effects on cognitive change
were attenuated by neuroimaging variables. Contrary
to hypotheses, CSF A␤ and CSF tau were observed to
have independent effects on neuroimaging and CSF tau
had a direct effect on baseline cognition independent
of brain structure and function [1507].
Small molecules preventing tau aggregation
TRx-0014 (methylthioninium chloride, methylene
blue, Rember; TauRx Therapeutics, Singapore, a spinout from the University of Aberdeen) (Fig. 15) is a
tau protein aggregation inhibitor. In August 2004, a
placebo-controlled, dose-ranging Phase II trial was
initiated in subjects (n = 275) with AD associated
dementia in the UK. The doses were 30, 60, or 100 mg
tid. In July 2007, a Phase II open-label continuation
study of two doses of 30 or 60 mg tid gelatin capsules started for 52 weeks. The drug reduced cognitive
decline by 81% over 1 year and no significant loss
of cognitive function was seen over 19 months [1508,
1509]. In November 2010, the EC granted the drug
Orphan status for frontotemporal dementia, progressive non-fluent aphasia and progressive supranuclear
palsy. In February 2012, an open-label trial in patients
with frontotemporal dementia was ongoing. For the
preclinical characterization, see [1510–1516]. Only
when levels of soluble tau protein were concomitantly
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
reduced by a very high concentration of methylene blue
cognitive improvement was observed in a mouse model
of human tauopathy [1517]. Methylene blue also inhibited the aggregation of A␤ [1518, 1519] (Thomson
Reuters Pharma, update of September 10, 2012).
LMT-X (TauRx Therapeutics, Singapore) is a
potential follow-up compound and prodrug of Rember.
In September 2012, a Phase III study for frontotemporal dementia began in 180 subjects for 12 months.
In October 2012 two global phase III studies were
initiated for AD. The first study will involve 833
patients with mild to moderate Alzheimer’s disease
over 12 months, while the second study will include
500 patients with mild Alzheimer’s disease over 18
months. The clinical trials will be conducted in parallel
and on a global basis including sites in Australia, Belgium, Canada, Finland, Germany, Italy, Russia, Spain,
Netherlands, Singapore, Malaysia, Taiwan, US and UK
(Thomson Reuters Pharma, update of November 21,
2012). The structure was not communicated.
PBT-2 (Prana Biotechnology, Parkville, Australia)
(see Fig. 9) is an oral zinc ionophore metal-protein
attenuating compound that reduced levels of soluble A␤ and tau hyperphosphorylation in a Phase IIa
study in AD patients. (Thomson Reuters Pharma,
update of October 2, 2012) See also Chapter 12. Metal
Chelators.
Tideglusib (NP-12, NP-031112; Nypta; Noscira,
previously known as Neuropharma, Madrid) (Fig. 15)
is a GSK-3␤ inhibitor in Phase II clinical trials for AD.
Results from the 309-patient study were expected by
October 2012. First positive results of a clinical pilot
study were reported [1520] (Thomson Reuters Pharma,
update of July 23, 2012). See also Part 2, Chapter 2.16.
Drugs interacting with GSK-3␤.
BMS-241027 (Bristol-Myers Squibb) is a small
molecule microtubule stabilizer aimed at preventing
the production of abnormal tau protein. A randomized,
double-blind, placebo-controlled Phase I study was initiated in patients with mild AD (expected n = 100) in
the US and in Europe in March 2012 (Thomson Reuters
Pharma, update of August 6, 2012). The structure was
not communicated.
PP2A stimulator (Se-015; Ve-015; Velacor Therapeutics, Victoria, Australia) is a selenium derivative
acting as protein phosphatase 2A (PP2A) stimulator
resulting in dephosphorylation of Akt kinase and tau.
By February 2011, a Phase I trial had been completed
and the company received the approval to initiate a
Phase IIa trial in AD patients in Australia (Thomson
Reuters Pharma, update of February 10, 2011). The
structure has not been communicated.
47
There are many compounds inhibiting tau aggregation in preclinical evaluation (in alphabetical
order):
A␤/tau protein aggregation inhibitors (CNRS,
FIST SA, Paris, France) are investigated for the potential treatment of AD (Thomson Reuters Pharma, update
of August 24, 2012). The structures of the compounds
were not communicated.
Astemizole and Lansoprazole have been found to
selectively interact with tau polymers [1521].
Berberine attenuated tau hyperphosphorylation in
HEK293 cells [1745].
Bezafibrate (Bezalip, Bezatol; Boehringer
Mannheim, now Roche, co-marketing with Kissei
Pharmaceuticals, launched 1977) (Fig. 15), a drug
for the treatment of hyperlipidemia, is a pan-PPAR
agonist, which improved behavioral deficits and tau
pathology in P301S mice exerting a preventive effect
[1522].
BLV-0703 (BLV-200703; Bioalvo, Lisbon, Portugal) (Fig. 15) is a tau aggregation inhibitor in
preclinical development (Thomson Reuters Pharma,
update of May 9, 2011).
Epothilone D improved microtubule density, axonal
integrity and cognition in a transgenic mouse model of
tauopathy [1523].
Fulvic acid inhibited aggregation and promoted the
disassembly of tau fibrils associated with AD [639].
Insulin intranasal ameliorated tau hyperphosphorylation in a rat model of type 2 diabetes [1524].
L-3-n-butylphthalide reduced tau phosphorylation
and improved cognitive deficits in A␤PP/PS1Alzheimer’s transgenic mice [1746].
NBB BSc3504 (TU Darmstadt and Max-PlanckUnit for Structural Molecular Biology Hamburg)
(Fig. 15) is a N -benzylidene-benzohydrazide
showing remarkable tau aggregation inhibition
(IC50 > 0.97 ␮M) and paired helical filament
depolymerization (DC50 > 1.14 ␮M), but poor
affinity towards A␤1-42 fibrils (IC50 > 33 ␮M) [1525].
NC-11813 (Eli Lilly and Nymirum, Ann Arbor, MI)
is an inhibitor of tau exon 10 splicing, which stabilized
the tau splice regulatory element (Thomson Reuters
Pharma, update of August 10, 2012). The structure was
not communicated.
NP-111001 derivatives (Noscira, Madrid) act as tau
phosphorylation inhibitors (Thomson Reuters Pharma,
update of January 12, 2012). The structures were not
communicated.
NPT-002 (NeuroPhage Pharmaceuticals, Cambridge, MA) targets A␤ and tau aggregates for the
potential treatment of AD (Thomson Reuters Pharma,
48
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 15. Molecules preventing tau aggregation.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
update of July 16, 2012). The structure was not communicated.
Protein phosphatase methylesterase 1 (PME1)
inhibitors (Signum Biosciences and GSK) are small
molecules blocking the enzyme which demethylates
PP2A. Normally PP2A is almost all methylated, but in
Alzheimer’s disease PP2A methylation is reduced in
half. The structural mechanism of demethylation and
inactivation of protein phosphatase 2a was described
[1747–1749] (Thomson Reuters Pharma, update
of November 15, 2012). The structures were not
communicated.
Protein phosphatase 2A stimulators (Cognosci,
Research Triangle Park, NC) inhibit the formation of
apoE/inhibitor 2 of PP2A (I2PP2A) complex. The topic protein phosphatases and AD was reviewed [1526,
1527] (Thomson Reuters Pharma, update of February
24, 2012). The structures were not communicated.
ReS3-T, ReS8-T, ReS10-T and ReS19-T
(reMYND, a spin-off from the University of Leuven,
Belgium and licensee Roche) are four series of tau
detoxifying compounds targeting tau-mediated cytotoxicity (Thomson Reuters Pharma, update of September 14, 2012). The structures were not communicated.
The ReS9-S7 and ReS12-S programs (reMYND,
a spin-off from the University of Leuven, Belgium
and licensee Roche) investigate the attenuation of
the cytotoxic effects of ␣-synuclein aggregation in
dopaminergic neurons for the potential treatment of
PD (Thomson Reuters Pharma, update of September
14, 2012). The structures were not communicated.
SIG-1012 (Cognion) and SIG-1106 (Signum Biosciences, Monmouth Junction NJ in collaboration with
Princeton Univ.) are phosphoprotein 2A modulators
and presumed to also include the PP2A methylesterase
1 inhibitor eicosanoyl-5-hydroxytryptamide (EHT), all
extracted from coffee and acting as tau aggregation
inhibitors. (Thomson Reuters Pharma, update of October 05, 2012). The structures were not communicated.
Small molecule Tau protein modulators
(Asceneuron, a spun-out of Merck Serono, Geneva,
Switzerland) are drugs for the potential treatment of
AD (Thomson Reuters Pharma, update of October 3,
2012). Structures were not disclosed.
Small molecule tau modulators (Yuma Therapeutics, Brookline, MA) target neurofibrillary tangles
resulting from abnormal forms of the protein tau
(Thomson Reuters Pharma, update of March 29, 2011).
Sodium selenate mitigated tau pathology and functional deficits in AD models [1528].
Tau aggregation inhibitors (Catholic University of
Leuven, Belgium) are currently in the preclinical Phase
49
(Thomson Reuters Pharma, update of July 30, 2012).
Structures were not communicated.
Tau aggregation inhibitors (ProteoTech, Kirkland, WA) have a potential for the treatment of AD
(Thomson Reuters Pharma, update of July 30, 2012).
Structures were not communicated.
Tau oligomer inhibitors (Oligomerix, New York,
NY) are presumably curcumin derivatives (Thomson
Reuters Pharma, update of April 24, 2012).
Tau phosphorylation inhibitors (ProQinase,
Freiburg im Breisgau, Germany) (Fig. 15) reduced
in vivo GSK-3␤ selective phosphorylation of
Ser396/Ser404 and Ser262 in the brains of triple
transgenic mice after i.p. administration. It appears
that the development was terminated (Thomson
Reuters Pharma update of October 11, 2012).
Therapeutic program (B & C Biopharm and
Equispharm, both South Korea) is targeting tau
kinase (Thomson Reuters Pharma update of May 18,
2012).
Thiamet-G (Simon Fraser University) is a potent
inhibitor of human O-GlcNAcase (Ki = 21 nM)
(Fig. 15) and efficiently reduced phosphorylation of
tau at Thr231, Ser396, and Ser422 in both rat cortex and hippocampus [1529–1533]. For commentaries,
see [1534, 1535]. See also Part 2, Chapter 2.27. Drugs
interacting with O-GlcNAcase.
THQ-4S and THQ-55 (Fig. 15) interact specifically
with oligomeric forms of tau inhibiting their assembly
into AD filaments [1536, 1537].
TRx-0237 (TauRx Therapeutics, Singapore) is the
lead compound of second-generation tau aggregation
inhibitors. Safety and efficacy studies in AD and frontotemporal dementia patients are planned for 2012
(Thomson Reuters Pharma, update of September 25,
2012). The structure was not communicated.
Tubastatin A (Fig. 15) is a potent and selective
HDAC6 inhibitor [1750]. Chronic tubastatin treatment
for two months decreased total tau levels in rtg4510
mice [1751].
Natural products as a source of tau-targeting drugs
were described [1538].
Excellent papers on small molecule inhibitors of
tau aggregation were published by researchers at
universities (in chronological order) 2004: [1539],
2005: [1540] (benzothiazoles such as N-744, Fig. 15),
[1541, 1542] 2006: [1543]; 2007: [1544–1550], 2009:
[1551–1555], 2010: [1556, 1557], 2011: [1558, 1559],
2012: [1560, 1561].
Excellent reviews on tau-focused drug discovery
for AD were presented (in chronological order)
2000: [1562]; 2002: [1563], 2006: [1564], 2007:
50
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1565], 2008: [1566–1569], 2009: [1570, 1571], 2010:
[1572–1574], 2011: [1575, 1576] [1577, 1578], 2012:
[1579–1581]. Interestingly, synergistic interactions
between repeats in tau protein and A␤ were described
[1582].
The development of the tau aggregation inhibitors
aminothienopyridazines (University of Pennsylvania), AZD-1080 (AstraZeneca), BPU-410 and
BPU-430 (Champions Biotechnology under license
from Johns Hopkins University), LDN-33960 (a
striatal-enriched protein tyrosine phosphatase (STEP)
inhibitor, Yale University), NHT-0112 (NeuroHitech), protein phosphatase methylesterase 1
(PME1) inhibitors (Scripps Research Institute and
Massachusetts Institute of Technology), SDGIT200801 and SDGII-T200801 (both Bioalvo),
SRN-003-556 (SIRENADE Pharmaceuticals) and of
TRx-0037 (TauRx) were terminated.
Ligands interacting with tau
T-777, T-807, and T-808 (Siemens Medical Solution Molecular Imaging) (Fig. 15) are tau-binding
molecules as PET tracers for the diagnosis of AD.
They are benz[4,5]imidazo[1,2-a]pyrimidines. 18 FT808 displayed a high level of binding affinity
(Kd = 22 nM) and good selectivity for tau aggregates
over A␤ plaques [1583] (Thomson Reuters Pharma,
update of September 19, 2011).
Novel in vivo tau imaging agents 18 F-THK-523
(University of Melbourne) [1584] and 11 C-THK-951
(Tohoku University) (both Fig. 15) were published
[1585] after preliminary results of 2005 [1752] (Thomson Reuters Pharma, update of September 219, 2012).
The University of Melbourne is investigating
18 F labeled arylquinoline derivatives, such as
18 F-THK-5105, 18 F-THK-5116, 18 F-THK-5117, and
18 F-THK-5125 for the potential use in imaging tau
deposition in neurofibrillary tangles for AD (Thomson Reuters Pharma, update of June 13, 2012). The
structures were not communicated.
Researchers of Amersham (GE Healthcare) published a patent describing ligands with an exceptional
selectivity to tau: compound 18 (Fig. 15): Kd = 0.9 nM
for tau and Kd = 30 ␮M for A␤1-40 [1586].
A 125 I-3-oxindole derivative stained neurofibrillary tangles in AD brain sections [1587].
Also bis(arylvinyl)pyrazines, -pyrimidines, and
-pyridazines were described as imaging agents for tau
fibrils and A␤ plaques [1588] as were 2-styrylindolium
based fluorescent probes [1753].
Research toward tau imaging was reviewed [1553,
1589, 1590] stating that ligand polarizability contributes to tau fibril binding affinity.
Vaccines against tau
Recombinant misfolded truncated tau protein vaccine (Axon Neurosciences, Vienna, Austria)
attenuated pathology in vivo in a transgenic rat model
of tauopathy (Thomson Reuters Pharma, update of
February 17, 2011).
RV-03 (Intellect Neurosciences, New York, NY)
is a peptide vaccine developed using the RECALLVAX technology targeting both the A␤ and a truncated
delta tau protein (Thomson Reuters Pharma, update of
August 21, 2012).
Phosphorylated tau peptides were used to immunize
transgenic mice to produce robust anti-neurofibrillary
tangle effects [1591].
The development of the chimeric peptide vaccine
RV-02 (Intellect Neurosciences) was terminated.
Antibodies against tau and α-synuclein
Humanized tau monoclonal antibodies (AC
Immune, Lausanne, Switzerland) had high specific
affinity binding to pTau. The compound was outlicensed to Genentech (Thomson Reuters Pharma,
update of June 19, 2012).
Lilly presented data on passive immunization with
anti-tau antibodies in two transgenic mouse models
[1754].
NI-105 (Biogen Idec, Weston, MA through the
acquisition of Panima, previously a subsidiary of
Neurimmune Therapeutics, Zurich Switzerland) is a
human recombinant monoclonal antibody targeted to
tau protein created using Neurimmune’s reverse translational medicine platform (Thomson Reuters Pharma,
update of May 4, 2012).
PD-0805 (Bioarctic Neuroscience, Stockholm,
Sweden) is a monoclonal antibody targeting ␣synuclein for the potential treatment of PD and DLB
(Thomson Reuters Pharma, update of September 2,
2011).
Pfizer presented the first X-ray structure of an avian
antibody to its cognate phosphopeptide pT231/pS235
at 1.9 Å resolution [1755].
T01-OX2 (Intellect Neurosciences, New York, NY)
is an antibody drug conjugate that consists of a mAb
targeting oligomeric forms of tau protein conjugated
to melatonin (Thomson Reuters Pharma, update of
August 17, 2012).
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
TauC3 monoclonal antibody (Intellect Neurosciences, New York, NY under license from
Northwestern University) is targeting the neoepitope
tauC3 (Thomson Reuters Pharma, update of September
20, 2012).
Tau protein modulator (iPierian, South San
Francisco, CA) is a monoclonal antibody for the
potential treatment of AD, frontotemporal dementia
and progressive supranuclear palsy (Thomson Reuters
Pharma, update of May 22, 2012).
Tau-targeted antibody therapy (Neotope Biosciences, South San Francisco, CA and Elan) is a
monoclonal antibody targeted to tau (Thomson Reuters
Pharma, update of August 13, 2012).
TOC-1 (Intellect Neurosciences, New York under
license from Northwestern University) is a tauoligomer-targeting monoclonal antibody [1592, 1593]
(Thomson Reuters Pharma, update of September 20,
2012).
The detection of naturally occurring anti-tau antibodies was described [1594].
Already in 1985 monoclonal antibodies to AD neurofibrillary tangles were described [1595]. Excellent
papers on passive immunization targeting pathological
phospho-tau protein were published (in chronological order) 2005: [1596], 2007: [1597], 2008: [1598,
1599], 2009: [1600, 1601], 2010: [1602, 1603], 2011:
[1604–1607], 2012: [1756].
The development of TTRY78F (University of
Porto), an anti-transthyretin monoclonal antibody, was
terminated.
STEM CELLS
Substantial progress has been achieved in research
of stem cells for the potential treatment of AD
communicated in chronological order: 2000: [1608],
2001: [1609–1611], 2006: [1612–1614], 2007: [1615,
1616], 2008: [1617, 1618], 2009: [1619–1622], 2010:
[1623–1630], 2011: [1631–1635], 2012: [1636–1642,
1757].
Human neural stem cells overexpressing choline
acetyltransferase restored cognitive function of kainicacid-induced learning and memory deficits in rats
[1643, 1644]. Neural stem cells reduced hippocampal tau and reelin accumulation [1645]. Intracerebral
transplantation of bone marrow-derived mesenchymal
stem cells reduced A␤ deposition and rescued memory deficits in AD mice by modulation of immune
responses [1626]. Neural stem cells improved cognition via BDNF in a transgenic model of AD
51
[1646–1648]. Human neural stem cells genetically
modified to express human NGF gene restored
cognition in mice [1649]. Human neural stem cells
genetically modified to overexpress BDNF promote
functional recovery and neuroprotection in a mouse
stroke model [1650]. Neural stem cells improved learning and memory in rats with AD [1651] and improved
neuronal survival in cultured postmortem brain tissue
from aged and AD patients [1652].
Induced pluripotent stem cells may be used to model
patient-specific AD in vitro [1653, 1654]. For a commentary, see [1655]; to model pathology in Down
syndrome [1656] and in HD [1657]. They may create new opportunities for disease modeling and drug
discovery [1758].
GDNF/BDNF-producing glial and brain-derived
stem cells (NurOwn; BrainStorm Cell Therapeutics,
New York, NY) is investigated as a potential treatment
of PD, sciatica, and multiple sclerosis [1658, 1659].
A Phase I/II clinical trial in ALS patients started in
June 2011 in Israel. In January 2012 positive data were
reported (Thomson Reuters Pharma, update of July 24,
2012).
Human neural stem cell therapy (HuCNS-SC;
StemCells, Newark, CA, formerly CytoTherapeutics
under license from NeuroSperes) is a proprietary transplantable human neural stem cell therapy for the
potential treatment of spinal cord injury, age-related
macular degeneration, and AD. Human neural stem
cells induced functional myelination in mice [1759]
and in the human brain [1760]. A Phase II trial for
spinal cord injury was initiated in Switzerland in March
2011. The neuroprotective effects in retinal degeneration were described [1660] (Thomson Reuters Pharma,
update of September 28, 2012).
Mesenchymal bone marrow-derived stem cell
therapy (Stemedica Cell Technologies, San Diego,
CA) is being developed for the intravenous treatment
of ischemic stroke in Phase I/II since February 2011
in the US (n = 35). The study was expected to be completed in February 2013 (Thomson Reuters Pharma,
update of April 11, 2012).
NSI-189 (Neuralstem, Rockville, MD, in collaboration with Japanese licensee Summit Pharmaceuticals)
(Fig. 16) is an orally bioavailable small-molecule neurogenesis stimulator in Phase I, which was completed
in October 2011. The FDA approved the Phase Ib trial
in December 2011 (three cohorts of eight patients each
). In June 2012, the first patients were dosed (Thomson
Reuters Pharma, update of September 28, 2012).
NSI-566RSC (Neuralstem, Rockville, MD) are
human neural stem cells including spinal cord stem
52
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fig. 16. A neurogenesis stimulator and two SV2A ligands.
cells for the potential injectable treatment of ALS,
stroke, HD, and AD. Long-distance growth and connectivity of neural stem cells after severe spinal cord
injury were investigated [1661]. A Phase I clinical
trial for ALS started in January 2010 in the US. The
results of a Phase I trial in 12 ALS patients receiving
lumbar intraspinal injection of neural stem cells were
described [1662] (Thomson Reuters Pharma, update of
September 28, 2012).
Neurostem-AD (Medipost, South Korea) is an
umbilical cord blood-derived mesenchymal stem cell
therapy, which regenerates nerve cells. A Phase I
trial has been initiated in February 2011 in patients
(expected n = 9) with dementia of AD-type (Thomson
Reuters Pharma, update of September 25, 2012).
There are several stem cell preparations in preclinical evaluation (in alphabetical order):
Adult mesenchymal precursor stem cell therapy
(Mesoblast, Melbourne, Australia and Cephalon, a
wholly-owned subsidiary of Teva) is evaluated for the
potential treatment of AD and PD and stroke (Thomson
Reuters Pharma, update of September 6, 2012).
Allogenic umbilical cord stem cell therapy
(U-CORD; CellPraxis Bioengenharia, Bela Vista,
Brazil) is investigated for the potential treatment
of Alzheimer’s disease. (Thomson Reuters Pharma,
update of November 07, 2012).
Brain-derived stem cell therapy (Celprogen, San
Pedro, CA, in collaboration with the Indiana University
School of Medicine) can be differentiated into neurons.
In vivo preclinical studies demonstrated improvement
in short and long term memory in AD experimental
models (Thomson Reuters Pharma, update of July 14,
2011).
CPG23NEUR (Celprogen, San Pedro, CA) derives
from cord blood stem cells, which are transdifferentiating into neuronal cells (Thomson Reuters
Pharma, update of January 30, 2012).
Glial progenitor cell therapy (Q Therapeutics, Salt
Lake City, UT) has the potential to replace myelin
on damaged neurons for the treatment of transverse
myelinitis, spinal cord injury, multiple sclerosis, PD,
and AD (Thomson Reuters Pharma, update of January
20, 2012).
Human neural progenitor cells (Cedars-Sinai
Medical Center, Los Angeles, CA), which secrete
growth factors including glial cell-derived neurotrophic factor, may be useful for the treatment of ALS
(Thomson Reuters Pharma, update of July 31, 2012).
Human umbilical cord blood cells (Saneron CCEL
Therapeutics, Tampa FL) are cerebroprotective agents
which showed cognition enhancing and amyloid-␤
reducing activities for the potential treatment of stroke
and Alzheimer’s disease (Thomson Reuters Pharma,
update of October 26, 2012).
NBI-18 (NeoCytex Biopharma, Covington, KY),
a heterocyclic pyrimidine derivative, is a stem cell
stimulator for the potential treatment of neurodegenerative diseases including ALS, AD, and PD (Thomson
Reuters Pharma, update of January 19, 2012). The
structure was not communicated.
Neural stem cell therapy (Stemedica Cell Technologies, San Diego, CA) is an allogeneic therapy
for the potential treatment of AD (Thomson Reuters
Pharma, update of February 22, 2012). Another
stem cell therapy is evaluated for spinal cord injury
(Thomson Reuters Pharma, update of February 28,
2012).
NeurotrophinCell (Living Cell Technologies,
Auckland, NZ) is an alginate-microencapsulated
porcine choroid plexus cell product for the potential
treatment of neurodegenerative diseases including HD,
PD, and dementia [1663, 1664] (Thomson Reuters
Pharma, update of May 16, 2012).
NGN-9079 (neural stem cell therapy; NeuroGeneration, Los Angeles, CA) is evaluated for the potential
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
treatment of AD. Transplantation of neuronal cells
into the brain was shown to improve and delay the
symptoms of AD in animal models (Thomson Reuters
Pharma, update of March 2, 2012).
ReN-004 (ReNeuron, Guildford, UK) is a neural
stem cell therapy for PD and AD (Thomson Reuters
Pharma, update of September 5, 2012).
ReN-005 (ReNeuron, Guildford, UK) is a neural
stem cell therapy for HD (Thomson Reuters Pharma,
update of December 24, 2010).
Stem cell therapeutics (Samaritan Pharmaceuticals, Las Vegas, NV) are non-embryonic neuronal stem
cell differentiation therapeutics including the naturally
occurring compounds SP-sc4 and SP-sc7 to induce
stem cell differentiation for the potential treatment of
AD (Thomson Reuters Pharma, update of March 16,
2011).
Allopregnanolone (University of Southern California, Los Angeles, CA) is a potent and highly efficacious
proliferative agent in vitro and in vivo of both rodent
and human neural stem cells [1665–1667].
Granulocyte colony-stimulating factor is known
to mobilize hematopoietic stem cells from the bone
marrow into the peripheral blood. Subcutaneous
administration of granulocyte colony-stimulating factor into two different A␤-induced AD mouse models
substantially rescued their cognitive/memory functions [1668].
Valproic acid can induce neurogenesis of neural
progenitor/stem cells both in vitro and in vivo via multiple signaling pathways [1669].
The development of GRNOPC-1 (Geron), oligodendrocyte precursor cells differentiated from a human
embryonic stem cell line that produce neurotrophic factors and remyelinate axons for the potential injectable
treatment of PD, stroke, AD, multiple sclerosis, and
spinal cord injury in Phase I since October 2010
was terminated. Also the development of the human
embryonic stem cell therapy (GRNIC-1, Geron),
the cell-based therapy MDA-200C (Medeia Therapeutics), NEBO-176 (Neuro Bioscience and RLI),
propentofylline (Endogenous Stem Cells Activators
(ESAI) under license from sanofi) and of stem cell
therapies for glaucoma, macular degeneration, PD,
traumatic brain injury, and vascular dementia (Stemedica) was terminated.
MISCELLANEOUS
Autophagy inducer JRP-900 (Prous Institute for
Biomedical Research, Barcelona) is investigated for
53
the potential treatment of neurodegenerative disease
including AD, ALS, HD, and PD (Thomson Reuters
Pharma, update of July 23, 2012). The structure
was not communicated. For reviews on autophagy in
Alzheimer’s disease and tauopathies see [1761–1764].
Cellular homeostasis modulator CNS-102 (Coyote Pharmaceuticals) acts on protein misfolding for
the potential treatment of AD, multiple sclerosis, and
ALS (Thomson Reuters Pharma, update of October 2,
2012). The structure was not communicated.
Glycan inhibitors (Stelic Institute, Tokyo) are
investigated for the potential treatment of Parkinson’s
and Alzheimer’s disease. An exhaustive review was
provided [1765]. (Thomson Reuters Pharma, update of
October 16, 2012). Structures were not communicated.
Macrophage migration inhibitory factor (MIF)
inhibitor INV-88 (Innovimmune Biotherapeutics,
New York) is investigated for the potential oral treatment of inflammatory diseases, central nervous system
diseases including Alzheimer’s disease and multiple
sclerosis and age-related macular degeneration (Thomson Reuters Pharma, update of October 18, 2012). The
structure was not communicated.
MicroRNA (miRNA) mimetics (University of
Göttingen, MBM Science) are evaluated for the potential diagnosis and treatment of memory impairment.
By June 2012, proof of concept was achieved in an
AD mouse model and in human AD patient samples.
The relationship of miRNAs in the brain and A␤ generation was discussed [1670] (Thomson Reuters Pharma,
update of August 7, 2012).
Proteasome-gating modulators are investigated
by Proteostasis Therapeutics, Cambridge, MA under
license from Harvard University for the potential treatment of neurodegenerative diseases including AD and
PD (Thomson Reuters Pharma, update of August 15,
2012).
Synaptic vesicle glycoprotein 2A (SV2A) ligand
levetiracetam (L-059, Keppra; UCB Pharma, Brussels, Belgium and Japanese licensee Otsuka) (Fig. 16)
is an antiepileptic drug launched in the US and EU
in 2000 and in Japan in 2010 [1671–1676]. It binds
to the same binding site as botulinum neurotoxin A
and tetanus neurotoxin [1677, 1678]. It is still unclear
how levetiracetam modulates SV2A’s function(s). It
inhibited presynaptic Ca2+ channels through an intracellular pathway [1679, 1680]. It may promote
glutamate uptake by increasing glutamate transporter
expression [1681]. There are hints that levetiracetam
may interact with GABAA receptors [1682–1684].
Levetiracetam had a positive impact on emotional
learning and memory in naı̈ve mice [1685] and
54
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
reversed cognitive deficits in hA␤PP transgenic mice
[1686]. Levetiracetam improved cognitive function in
drug-naı̈ve epilepsy patients [1687] and in children
aged 4 to 16 years [1688]. The sales of levetiracetam
reported by UCB for 2011 were USD 1,345 million and
by Otsuka, USD 60.5. An injectable formulation was
launched in the US in August 2006, an extended release
formulation in September 2008 (Thomson Reuters
Pharma, update of October 1, 2012).
Low-dose therapy Levetiracetam (AgeneBio,
Carmel, IN under license from John Hopkins University) is investigated for the potential treatment
of amnestic MCI (aMCI) in Phase II clinical trials since December 2009 in 144 aMCI patients in
the US. Reduction of hippocampal hyperactivity in
aMCI patients by using a low dose of levetiracetam
improved cognition [1766]. It appears that the development was terminated (Thomson Reuters Pharma,
update of September 7, 2011).
Brivaracetam (UCB-34714; Rikelta; UCB Pharma,
Brussels, Belgium) (Fig. 16), the n-propyl analogue
of levetiracetam, is an orally active ligand of synaptic
vesicle protein 2A (SV2A) currently in Phase III clinical trials for the treatment of epilepsy since November
2008 (n = 600). The study is expected to complete in
June 2015 [1689, 1690]. Its binding characteristics as
a high affinity SV2A ligand in rat, mouse and human
brain were reported [1691] as was its effect on the
inhibition of Na+ currents [1692]. Its neurocognitive
effects were similar to the ones of levetiracetam [1693,
1694] (Thomson Reuters Pharma, update of August 8,
2012).
The development of the second Phase III monoclonal antibody bapineuzumab (Janssen Alzheimer
Immunotherapy and Pfizer) was terminated.
The Phase III clinical trials of other A␤ PET
imaging agents, 18 F-florbetaben (Piramal) and 18 Fflutemetamol (GE Healthcare), may be successfully
completed by next year. The completion of Phase
III clinical trials of the VMAT2 PET ligand 18 Fflorbenazine (Avid Radiopharmaceuticals, Lilly) is
planned for September 2014.
Phase II clinical trials of other disease modifying drugs, of monoclonal antibodies against A␤
gantenerumab, crenezumab, GSK-93377A, intravenous immune globulin, and octagam, of vaccines
against A␤ AD-02, CAD-106, and vanutide cridificar and the PET ligand 18 F-AZD-4694 (Navidea)
will require several years. This applies also for the
Phase II clinical trials of small molecules preventing
A␤ aggregation or inhibiting formation of transthyretin
amyloid fibrils, such as doxycycline hyclate, ELND005, and SOM-0226 or preventing tau aggregation,
such as PBT-2, tideglusib, and TRx-0014.
Concerning drugs for palliative treatment of AD,
two Phase III compounds are currently frontrunners,
DP-b99 (a calcium and zinc chelator) and SK-PCB70M (a natural product) followed by 22 Phase II
compounds, RV-208 (a gene expression stimulator),
ARC-029 and ZSET-1446/ST-101 (calcium channel
blockers), CERE-110, GM-607, PYM-50058, and
T-817MA (trophic factor stimulators), circadin, KD501, PPL, PTX-200, resveratrol, RPh-201 (natural
products), LSL-001, N-251, PF-03049423, TRM189, VI-1121 (nootropics), davunetide, AM-111,
etanercept, and FGL (peptides).
CONCLUSION
DISCLOSURE STATEMENT
Two products were launched in 2012: tafamidis
(Vyndaquel, Pfizer) for the treatment of transthyretin
familial amyloid polyneuropathy in Europe in March
and 18 F-florbetapir (Amyvid; Avid Radiopharmaceuticals, Lilly) as a PET imaging agent to estimate
A␤ neuritic plaque density in patients with cognitive
impairment in the US in June.
Phase III Alzheimer’s disease trials of a disease
modifying drug, the monoclonal antibody against A␤
solanezumab (Lilly), are close to completion. First
results showed that solanezumab failed to meet the cognitive and functional primary endpoints. But it showed
a significant reduction in cognitive decline in patients
with mild AD. For a commentary, see [1695]. The
open-label EXPEDITION-EXT extension trial, which
is fully enrolled, is continuing as planned.
Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1543).
REFERENCES
[1]
[2]
[3]
Giurgea C (1972) [Pharmacology of integrative activity of
the brain. Attempt at nootropic concept in psychopharmacology. Actual Pharmacol (Paris) 25, 115-156.
Giurgea C (1973) The “nootropic” approach to the pharmacology of the integrative activity of the brain. Cond Reflex
8, 108-115.
Millan MJ, Agid Y, Brune M, Bullmore ET, Carter CS,
Clayton NS, Connor R, Davis S, Deakin B, DeRubeis RJ,
Dubois B, Geyer MA, Goodwin GM, Gorwood P, Jay TM,
Joels M, Mansuy IM, Meyer-Lindenberg A, Murphy D,
Rolls E, Saletu B, Spedding M, SweeneyJ, Whittington
M, Young LJ (2012) Cognitive dysfunction in psychiatric
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
disorders: Characteristics, causes and the quest for
improved therapy. Nat Rev Drug Discov 11, 141-168.
Froestl W, Maitre L (1989) The families of cognition
enhancers. Pharmacopsychiatry 22(Suppl 2), 54-100.
Froestl W, Muhs A, Pfeifer A (2012) Cognitive Enhancers
(Nootropics). Part 1: Drugs interacting with receptors. J
Alzheimers Dis 32, 793-887.
Citron M (2004) Strategies for disease modification in
Alzheimer’s disease. Nat Rev Neurosci 5, 677-685.
Pangalos MN, Jacobsen SJ, Reinhart PH (2005) Disease
modifying strategies for the treatment of Alzheimer’s disease targeted at modulating levels of the beta-amyloid
peptide. Biochem Soc Trans 33, 553-558.
Hull M, Berger M, Heneka M (2006) Disease-modifying
therapies in Alzheimer’s disease: How far have we come?
Drugs 66, 2075-2093.
Vellas B, Andrieu S, Sampaio C, Wilcock G (2007)
Disease-modifying trials in Alzheimer’s disease: A European task force consensus. Lancet Neurol 6, 56-62.
Sadowski M, Wisniewski T (2007) Disease modifying
approaches for Alzheimer’s pathology. Curr Pharm Des
13, 1943-1954.
Salloway S, MintzerJ, Weiner MF, Cummings JL (2008)
Disease-modifying therapies in Alzheimer’s disease.
Alzheimers Dement 4, 65-79.
Sabbagh MN, Richardson S, Relkin N (2008) Diseasemodifying approaches to Alzheimer’s disease: Challenges and opportunities-Lessons from donepezil therapy.
Alzheimers Dement 4, S109-S118.
Vellas B, Coley N, Andrieu S (2008) Disease modifying
trials in Alzheimer’s disease: Perspectives for the future. J
Alzheimers Dis 15, 289-301.
Duara R, Barker W, Loewenstein D, Bain L (2009) The
basis for disease-modifying treatments for Alzheimer’s
disease: The Sixth Annual Mild Cognitive Impairment
Symposium. Alzheimers Dement 5, 66-74.
Panza F, Solfrizzi V, Frisardi V, Capurso C, D’Introno A,
Colacicco AM, Vendemiale G, Capurso A, Imbimbo BP
(2009) Disease-modifying approach to the treatment of
Alzheimer’s disease: From alpha-secretase activators to
gamma-secretase inhibitors and modulators. Drugs Aging
26, 537-555.
Citron M (2010) Alzheimer’s disease: Strategies for disease modification. Nat Rev Drug Discov 9, 387-398.
Frisardi V, Solfrizzi V, Imbimbo PB, Capurso C, D’Introno
A, Colacicco AM, Vendemiale G, Seripa D, Pilotto A,
Capurso A, Panza F (2010) Towards disease-modifying
treatment of Alzheimer’s disease: Drugs targeting betaamyloid. Curr Alzheimer Res 7, 40-55.
Dash SK (2011) Future targeted disease modifying drugs
for Alzheimer’s disease. Recent Pat CNS Drug Discov 6,
65-76.
Galimberti D, Scarpini E (2010) Treatment of Alzheimer’s
disease: Symptomatic and disease-modifying approaches.
Curr Aging Sci 3, 46-56.
Galimberti D, Scarpini E (2011) Disease-modifying treatments for Alzheimer’s disease. Ther Adv Neurol Disord 4,
203-216.
Galimberti D, Scarpini E (2011) Alzheimer’s disease:
From pathogenesis to disease-modifying approaches. CNS
Neurol Disord Drug Targets 10, 163-174.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F
(2012) New pharmacological strategies for treatment of
Alzheimer’s disease: Focus on disease modifying drugs.
Br J Clin Pharmacol 73, 504-517.
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
55
Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Logroscino G, Santamato A, Greco A, Seripa D, Pilotto A
(2012) Immunotherapy for Alzheimer’s disease: From
anti-beta-amyloid to tau-based immunization strategies.
Immunotherapy 4, 213-238.
Cummings JL, Doody R, Clark C (2007) Diseasemodifying therapies for Alzheimer disease: Challenges to
early intervention. Neurology 69, 1622-1634.
Cummings JL (2008) Optimizing phase II of drug development for disease-modifying compounds. Alzheimers
Dement 4, S15-S20.
Cummings JL (2009) Defining and labeling diseasemodifying treatments for Alzheimer’s disease. Alzheimers
Dement 5, 406-418.
Jiang T, Yu JT, Tan L (2012) Novel disease-modifying
therapies for Alzheimer’s disease. J Alzheimers Dis 31,
475-492.
Lee KS, Chung JH, Choi TK, Suh SY, Oh BH, Hong
CH (2009) Peripheral cytokines and chemokines in
Alzheimer’s disease. Dement Geriatr Cogn Disord 28,
281-287.
Gitter BD, Cox LM, Rydel RE, May PC (1995) Amyloid
beta peptide potentiates cytokine secretion by interleukin1 beta-activated human astrocytoma cells. Proc Natl Acad
Sci U S A 92, 10738-10741.
Harries LW, Bradley-Smith RM, Llewellyn DJ, Pilling
LC, Fellows A, Henley W, Hernandez D, Guralnik
JM, Bandinelli S, Singleton A, Ferrucci L, Melzer D
(2012) Leukocyte CCR2 expression is associated with
mini-mental state examination score in older adults. Rejuvenation Res 15, 395-404.
Ralay Ranaivo H, Craft JM, Hu W, Guo L, Wing LK, Van
Eldik LJ, Watterson DM (2006) Glia as a therapeutic target: Selective suppression of human amyloid-beta-induced
upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci 26, 662-670.
Bachstetter AD, Norris CM, Sompol P, Wilcock DM,
Goulding D, Neltner JH, St CD, Watterson DM, Van
Eldik LJ (2012) Early stage drug treatment that normalizes
proinflammatory cytokine production attenuates synaptic
dysfunction in a mouse model that exhibits age-dependent
progression of Alzheimer’s disease-related pathology. J
Neurosci 32, 10201-10210.
Hu W, Ralay RH, Roy SM, Behanna HA, Wing LK,
Munoz L, Guo L, Van Eldik LJ, Watterson DM (2007)
Development of a novel therapeutic suppressor of brain
proinflammatory cytokine up-regulation that attenuates
synaptic dysfunction and behavioral deficits. Bioorg Med
Chem Lett 17, 414-418.
Karpus WJ, Reynolds N, Behanna HA, Van Eldik LJ, Watterson DM (2008) Inhibition of experimental autoimmune
encephalomyelitis by a novel small molecular weight
proinflammatory cytokine suppressing drug. J Neuroimmunol 203, 73-78.
Lloyd E, Somera-Molina K, Van Eldik LJ, Watterson DM,
Wainwright MS (2008) Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury
administration of a novel small molecule improves
long-term neurologic outcome in a mouse model of traumatic brain injury. J Neuroinflammation 5, 28.
Somera-Molina KC, Robin B, Somera CA, Anderson C,
Stine C, Koh S, Behanna HA, Van Eldik LJ, Watterson DM, Wainwright MS (2007) Glial activation links
early-life seizures and long-term neurologic dysfunction:
Evidence using a small molecule inhibitor of proin-
56
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
flammatory cytokine upregulation. Epilepsia 48, 17851800.
O’Hare E, Scopes DI, Treherne JM, Monaghan J, Palmer
PM, Amijee H, Kim EM (2011) Novel anti-inflammatory
compound SEN1176 alleviates behavioral deficits induced
following bilateral intrahippocampal injection of aggregated amyloid-beta. J Alzheimers Dis 25, 219-229.
Shi JQ, Wang BR, Jiang WW, Chen J, Zhu YW, Zhong
LL, Zhang YD, Xu J (2011) Cognitive improvement with
intrathecal administration of infliximab in a woman with
Alzheimer’s disease. J Am Geriatr Soc 59, 1142-1144.
Bacher M, Dodel R, Aljabari B, Keyvani K, Marambaud
P, Kayed R, Glabe C, Goertz N, Hoppmann A, Sachser
N, Klotsche J, Schnell S, Lewejohann L, Al-Abed Y
(2008) CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of
Alzheimer’s disease. J Exp Med 205, 1593-1599.
Bach JP, Mengel D, Wahle T, Kautz A, Balzer-Geldsetzer
M, Al-Abed Y, Dodel R, Bacher M (2011) The role of CNI1493 in the function of primary microglia with respect to
amyloid-beta. J Alzheimers Dis 26, 69-80.
Nilsson P, Iwata N, Muramatsu S, Tjernberg LO, Winblad B, Saido TC (2010) Gene therapy in Alzheimer’s
disease–potential for disease modification. J Cell Mol Med
14, 741-757.
Goldberg TE, Weinberger DR (2004) Genes and the parsing of cognitive processes. Trends Cogn Sci 8, 325-335.
Zetterstrom TS, Pei Q, Madhav TR, Coppell AL, Lewis
L, Grahame-Smith DG (1999) Manipulations of brain
5-HT levels affect gene expression for BDNF in rat brain.
Neuropharmacology 38, 1063-1073.
Coppell AL, Pei Q, Zetterstrom TS (2003) Bi-phasic
change in BDNF gene expression following antidepressant
drug treatment. Neuropharmacology 44, 903-910.
Bourhis E, Maheux J, Rouillard C, Levesque D (2008)
Extracellular signal-regulated kinases (ERK) and protein
kinase C (PKC) activities are involved in the modulation
of Nur77 and Nor-1 expression by dopaminergic drugs. J
Neurochem 106, 875-888.
Uusi-Oukari M, Korpi ER (2010) Regulation of GABA(A)
receptor subunit expression by pharmacological agents.
Pharmacol Rev 62, 97-135.
Southwell AL, Patterson PH (2011) Gene therapy in mouse
models of huntington disease. Neuroscientist 17, 153162.
Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K,
Azuma J, Sawa Y, Matsuda H, Kaneda Y, Ogihara T (2004)
Safety evaluation of clinical gene therapy using hepatocyte
growth factor to treat peripheral arterial disease. Hypertension 44, 203-209.
Makino H, Aoki M, Hashiya N, Yamasaki K, Azuma J,
Sawa Y, Kaneda Y, Ogihara T, Morishita R (2012) Longterm follow-up evaluation of results from clinical trial
using hepatocyte growth factor gene to treat severe peripheral arterial disease. Arterioscler Thromb Vasc Biol 32,
2503-2509.
Anonymous (2011) Rvx 208. Drugs R D 11, 207-213.
Nicholls SJ, Gordon A, Johannson J, Ballantyne CM,
Barter PJ, Brewer HB, Kastelein JJ, Wong NC, Borgman
MR, Nissen SE (2012) ApoA-I induction as a potential
cardioprotective strategy: Rationale for the SUSTAIN and
ASSURE studies. Cardiovasc Drugs Ther 26, 181-187.
Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S,
Chatur S, Wagner GS, Hansen HC, Chiacchia FS, Johansson J, Krimbou L, Wong NC, Genest J (2010) RVX-208:
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
A small molecule that increases apolipoprotein A-I and
high-density lipoprotein cholesterol in vitro and in vivo. J
Am Coll Cardiol 55, 2580-2589.
McNeill E (2010) RVX-208, a stimulator of apolipoprotein AI gene expression for the treatment of cardiovascular
diseases. Curr Opin Investig Drugs 11, 357-364.
Davidson MH (2011) Apolipoprotein A-I therapy promise,
challenges, and disappointment. J Am Coll Cardiol 57,
1120-1121.
Nicholls SJ, Gordon A, Johansson J, Wolski K, Ballantyne CM, Kastelein JJ, Taylor A, Borgman M, Nissen
SE (2011) Efficacy and safety of a novel oral inducer of
apolipoprotein a-I synthesis in statin-treated patients with
stable coronary artery disease a randomized controlled
trial. J Am Coll Cardiol 57, 1111-1119.
Shah PK (2011) Atherosclerosis: Targeting endogenous
apo A-I –a new approach for raising HDL. Nat Rev Cardiol
8, 187-188.
Hudry E, Van DD, Kulik W, De Deyn PP, Stet FS, Ahouansou O, Benraiss A, Delacourte A, Bougneres P, Aubourg P,
Cartier N (2010) Adeno-associated virus gene therapy with
cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse
models of Alzheimer’s disease. Mol Ther 18, 44-53.
Yang SY, He XY, Miller D (2007) HSD17B10: A gene
involved in cognitive function through metabolism of
isoleucine and neuroactive steroids. Mol Genet Metab 92,
36-42.
Hafez DM, Huang JY, Richardson JC, Masliah E, Peterson
DA, Marr RA (2012) F-spondin gene transfer improves
memory performance and reduces amyloid-beta levels in
mice. Neuroscience 223, 465-472.
Chiba T, Yamada M, Hashimoto Y, Sato M, Sasabe J,
Kita Y, Terashita K, Aiso S, Nishimoto I, Matsuoka
M (2005) Development of a femtomolar-acting humanin
derivative named colivelin by attaching activity-dependent
neurotrophic factor to its N terminus: Characterization
of colivelin-mediated neuroprotection against Alzheimer’s
disease-relevant insults in vitro and in vivo. J Neurosci 25,
10252-10261.
Chiba T, Nishimoto I, Aiso S, Matsuoka M (2007)
Neuroprotection against neurodegenerative diseases:
Development of a novel hybrid neuroprotective peptide
Colivelin. Mol Neurobiol 35, 55-84.
Matsuoka M, Hashimoto Y, Aiso S, Nishimoto I (2006)
Humanin and colivelin: Neuronal-death-suppressing peptides for Alzheimer’s disease and amyotrophic lateral
sclerosis. CNS Drug Rev 12, 113-122.
Yamada M, Chiba T, Sasabe J, Terashita K, Aiso S, Matsuoka M (2008) Nasal Colivelin treatment ameliorates
memory impairment related to Alzheimer’s disease. Neuropsychopharmacology 33, 2020-2032.
Arakawa T, Niikura T, Arisaka F, Kita Y (2008) Activitydependent neurotrophic factor, ADNF, determines the
structure characteristics of Colivelin, a fusion protein of
ADNF9 and Humanin analog. J Pept Sci 14, 631-636.
Hashimoto Y, Ito Y, Niikura T, Shao Z, Hata M, Oyama
F, Nishimoto I (2001) Mechanisms of neuroprotection
by a novel rescue factor humanin from Swedish mutant
amyloid precursor protein. Biochem Biophys Res Commun
283, 460-468.
Maximov V, Martynenko A, Hunsmann G, Tarantul V
(2002) Mitochondrial 16S rRNA gene encodes a functional
peptide, a potential drug for Alzheimer’s disease and target
for cancer therapy. Med Hypotheses 59, 670-673.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
Tortosa E, Santa-Maria I, Moreno F, Lim F, Perez M, Avila
J (2009) Binding of Hsp90 to tau promotes a conformational change and aggregation of tau protein. J Alzheimers
Dis 17, 319-325.
Salminen A, Ojala J, Kaarniranta K, Hiltunen M, Soininen H (2011) Hsp90 regulates tau pathology through
co-chaperone complexes in Alzheimer’s disease. Prog
Neurobiol 93, 99-110.
Vilenchik M, Solit D, Basso A, Huezo H, Lucas B, He H,
Rosen N, Spampinato C, Modrich P, Chiosis G (2004) Targeting wide-range oncogenic transformation via PU24FCl,
a specific inhibitor of tumor Hsp90. Chem Biol 11, 787797.
He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, Wu
N, Immormino RM, Gewirth DT, Chiosis G (2006) Identification of potent water soluble purine-scaffold inhibitors
of the heat shock protein 90. J Med Chem 49, 381-390.
Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo
Y, Wu N, de SE, White J, Gross SS, Ma Y, Varticovski
L, Melnick A, Chiosis G (2009) Hsp90 inhibitor PU-H71,
a multimodal inhibitor of malignancy, induces complete
responses in triple-negative breast cancer models. Proc
Natl Acad Sci U S A 106, 8368-8373.
Luo W, Dou F, Rodina A, Chip S, Kim J, Zhao Q, Moulick
K, Aguirre J, Wu N, Greengard P, Chiosis G (2007) Roles
of heat-shock protein 90 in maintaining and facilitating
the neurodegenerative phenotype in tauopathies. Proc Natl
Acad Sci U S A 104, 9511-9516.
Cole P, Vasiliou S, Mormeno D, Rosa E (2009) Medicinal
chemistry selections from the 237th American Chemical
Society National Meeting & Exposition. Drugs Future 34,
509-520.
Taldone T, Chiosis G (2009) Purine-scaffold Hsp90
inhibitors. Curr Top Med Chem 9, 1436-1446.
Taldone T, Zatorska D, Patel PD, Zong H, Rodina A, Ahn
JH, Moulick K, Guzman ML, Chiosis G (2011) Design,
synthesis, and evaluation of small molecule Hsp90 probes.
Bioorg Med Chem 19, 2603-2614.
Biamonte MA, Shi J, Hong K, Hurst DC, Zhang L, Fan
J, Busch DJ, Karjian PL, Maldonado AA, Sensintaffar JL,
Yang YC, Kamal A, Lough RE, Lundgren K, Burrows
FJ, Timony GA, Boehm MF, Kasibhatla SR (2006) Orally
active purine-based inhibitors of the heat shock protein 90.
J Med Chem 49, 817-828.
Dickey CA, Dunmore J, Lu B, Wang JW, Lee WC, Kamal
A, Burrows F, Eckman C, Hutton M, Petrucelli L (2006)
HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS
(MARK) sites. FASEB J 20, 753-755.
Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM,
Dunmore J, Ash P, Shoraka S, Zlatkovic J, Eckman CB,
Patterson C, Dickson DW, Nahman NS Jr, Hutton M, Burrows F, Petrucelli L (2007) The high-affinity HSP90-CHIP
complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest 117, 648-658.
Oddo S, Caccamo A, Tseng B, Cheng D, Vasilevko V,
Cribbs DH, LaFerla FM (2008) Blocking Abeta42 accumulation delays the onset and progression of tau pathology
via the C terminus of heat shock protein70-interacting protein: A mechanistic link between Abeta and tau pathology.
J Neurosci 28, 12163-12175.
Patterson KR, Ward SM, Combs B, Voss K, Kanaan NM,
Morfini G, Brady ST, Gamblin TC, Binder LI (2011) Heat
shock protein 70 prevents both tau aggregation and the
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
[93]
[94]
[95]
57
inhibitory effects of preexisting tau aggregates on fast
axonal transport. Biochemistry 50, 10300-10310.
Wilhelmus MM, de Waal RM, Verbeek MM (2007) Heat
shock proteins and amateur chaperones in amyloid-Beta
accumulation and clearance in Alzheimer’s disease. Mol
Neurobiol 35, 203-216.
Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem
53, 4585-4602.
Yarbrough GG (1983) Minireview. Thyrotropin releasing
hormone and CNS cholinergic neurons. Life Sci 33, 111118.
Mellow AM, Sunderland T, Cohen RM, Lawlor BA, Hill
JL, Newhouse PA, Cohen MR, Murphy DL (1989) Acute
effects of high-dose thyrotropin releasing hormone infusions in Alzheimer’s disease. Psychopharmacology (Berl)
98, 403-407.
Molchan SE, Mellow AM, Lawlor BA, Weingartner HJ,
Cohen RM, Cohen MR, Sunderland T (1990) TRH attenuates scopolamine-induced memory impairment in humans.
Psychopharmacology (Berl) 100, 84-89.
Khan A, Mirolo MH, Claypoole K, Bhang J, Cox G, Horita
A, Tucker G (1994) Effects of low-dose TRH on cognitive
deficits in the ECT postictal state. Am J Psychiatry 151,
1694-1696.
Urayama A, Yamada S, Hirano K, Deguchi Y,
Kimura R (2001) Brain receptor binding characteristics and pharmacokinetic-pharmacodynamic analysis of
thyrotropin-releasing hormone analogues. Life Sci 70, 647657.
Urayama A, Yamada S, Kimura R, Zhang J, Watanabe Y
(2002) Neuroprotective effect and brain receptor binding
of taltirelin, a novel thyrotropin-releasing hormone (TRH)
analogue, in transient forebrain ischemia of C57BL/6J
mice. Life Sci 72, 601-607.
Tanabe M, Tokuda Y, Takasu K, Ono K, Honda M,
Ono H (2007) The synthetic TRH analogue taltirelin
exerts modality-specific antinociceptive effects via distinct
descending monoaminergic systems. Br J Pharmacol 150,
403-414.
Grigorova M, Sherwin BB, Tulandi T (2006) Effects
of treatment with leuprolide acetate depot on working
memory and executive functions in young premenopausal
women. Psychoneuroendocrinology 31, 935-947.
Bowen RL, Verdile G, Liu T, Parlow AF, Perry G,
Smith MA, Martins RN, Atwood CS (2004) Luteinizing hormone, a reproductive regulator that modulates the
processing of amyloid-beta precursor protein and amyloidbeta deposition. J Biol Chem 279, 20539-20545.
Casadesus G, Webber KM, Atwood CS, Pappolla MA,
Perry G, Bowen RL, Smith MA (2006) Luteinizing hormone modulates cognition and amyloid-beta deposition in
Alzheimer APP transgenic mice. Biochim Biophys Acta
1762, 447-452.
Casadesus G, Zhu X, Atwood CS, Webber KM, Perry G,
Bowen RL, Smith MA (2004) Beyond estrogen: Targeting
gonadotropin hormones in the treatment of Alzheimer’s
disease. Curr Drug Targets CNS Neurol Disord 3, 281-285.
Casadesus G, Atwood CS, Zhu X, Hartzler AW, Webber
KM, Perry G, Bowen RL, Smith MA (2005) Evidence for
the role of gonadotropin hormones in the development of
Alzheimer disease. Cell Mol Life Sci 62, 293-298.
Meethal SV, Smith MA, Bowen RL, Atwood CS (2005)
The gonadotropin connection in Alzheimer’s disease.
Endocrine 26, 317-326.
58
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105]
[106]
[107]
[108]
Wilson AC, Meethal SV, Bowen RL, Atwood CS (2007)
Leuprolide acetate: A drug of diverse clinical applications.
Expert Opin Investig Drugs 16, 1851-1863.
Baker LD, Barsness SM, Borson S, Merriam GR, Friedman SD, Craft S, Vitiello MV (2012) Effects of growth
hormone-releasing hormone on cognitive function in
adults with mild cognitive impairment and healthy older
adults: Results of a controlled trial. Arch Neurol 69, 14201429.
Mori M, Iriuchijima T, Yamada M, Murakami M,
Kobayashi S (1991) A novel TRH analog, YM14673, stimulates intracellular signaling systems in the brain more
potently than predicted by its pituitary actions. Res Commun Chem Pathol Pharmacol 71, 17-26.
Yamamoto M, Ozawa Y, Takeuchi H (1993) Effects of YM14673, a new thyrotropin-releasing hormone analogue, on
impaired learning of passive avoidance in mice. Arch Int
Pharmacodyn Ther 321, 5-13.
Matsushita M, Yonemori F, Hamada A, Toide K, Iwata K
(1995) Effect of JTP-2942, a novel thyrotropin-releasing
hormone analogue, on pentobarbital-induced anesthesia in
rats. Eur J Pharmacol 276, 177-182.
Katsumata T, Katayama Y, Yonemori H, Muramatsu H,
Otori T, Nishiyama Y, Yamada H, Nakamura H, Terashi
A (2001) Delayed administration of JTP-2942, a novel
thyrotropin-releasing hormone analogue, improves cerebral blood flow and metabolism in rat postischaemic brain.
Clin Exp Pharmacol Physiol 28, 48-54.
Katsumata T, Katayama Y, Ootori T, Muramatsu H,
Nishiyama Y, Nakamura H, Seta T, Terashi A (2001)
Effect of long-term administration of JTP-2942, a novel
thyrotropin-releasing hormone analogue, on neurological
outcome, local cerebral blood flow and glucose utilization in a rat focal cerebral ischemia. Brain Res 901,
62-70.
Itoh Y, Ogasawara T, Mushiroi T, Yamazaki A, Ukai Y,
Kimura K (1994) Effect of NS-3, a thyrotropin-releasing
hormone analog, on in vivo acetylcholine release in rat
brain: Regional differences and its sites of action. J Pharmacol Exp Ther 271, 884-890.
Bristow LJ, Bennett GW (1989) Effect of chronic intraaccumbens administration of the TRH analogue CG3509
on histamine-induced behaviour in the rat. Br J Pharmacol
97, 745-752.
Fone KC, Johnson JV, Bennett GW, Marsden CA (1989)
Involvement of 5-HT2 receptors in the behaviours produced by intrathecal administration of selected 5-HT
agonists and the TRH analogue (CG 3509) to rats. Br J
Pharmacol 96, 599-608.
Fone KC, Johnson JV, Marsden CA, Bennett GW
(1989) Comparative behavioural and biochemical effects
of repeated intrathecal administration of thyrotrophinreleasing hormone (TRH) or two analogues of TRH in
adult rats. Neuropharmacology 28, 867-875.
Parnetti L, Ambrosoli L, Abate G, Azzini C, Balestreri
R, Bartorelli L, Bordin A, Crepaldi G, Cristianini G,
Cucinotta D, et al. (1995) Posatirelin for the treatment of late-onset Alzheimer’s disease: A double-blind
multicentre study vs citicoline and ascorbic acid. Acta
Neurol Scand 92, 135-140.
Parnetti L, Ambrosoli L, Agliati G, Caratozzolo P, Fossati
L, Frattola L, Martucci N, Murri L, Nappi G, Puca FM, Poli
A, Girardello R, Senin U (1996) Posatirelin in the treatment of vascular dementia: A double-blind multicentre
study vs placebo. Acta Neurol Scand 93, 456-463.
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
Gasbarrini G, Stefanini G, Addolorato G, Foschi F, Ricci C,
Bertolotti P, Voltolini G, Bonavita E, Bertoncelli R, Renzi
G, Bianchini G, Bonaiuto S, Giannandrea E, Cavassini G,
Mazzini V, Chioma V, Marzara G, D’Addetta G, Totaro
G, Dalmonte E, Tassini D, Giungi F, De NC, Di FG,
Tessitore A, Guadagnino M, Tessitore E, Spina P, Luppi
M, Bignamini A, Peracino L, Fiorentino M, Beun-Garbe
D, Poli A, Ambrosoli L, Girardello R (1998) Posatirelin
for the treatment of degenerative and vascular dementia:
Results of explanatory and pragmatic efficacy analyses.
Arch Gerontol Geriatr 26, 33-47.
Suzuki T, Fujimoto K, Oohata H, Kawashima K (1989)
Effects of TRH and DN-1417 on high potassium-evoked
acetylcholine release from rat basal forebrain slices determined directly by radioimmunoassay. Gen Pharmacol 20,
239-242.
Ballard TM, Hunter AJ, Bennett GW (1996) Effect of
a thyrotrophin-releasing hormone analogue, RX77368,
on AMPA-induced septal-hippocampal lesioned rats in
an operant delayed non-matching to position test. Psychopharmacology (Berl) 127, 265-275.
Itkin A, Dupres V, Dufrene YF, Bechinger B, Ruysschaert
JM, Raussens V (2011) Calcium ions promote formation of
amyloid beta-peptide (1-40) oligomers causally implicated
in neuronal toxicity of Alzheimer’s disease. PLoS One 6,
e18250.
Kawahara M, Ohtsuka I, Yokoyama S, Kato-Negishi
M, Sadakane Y (2011) Membrane incorporation, channel formation, and disruption of calcium homeostasis by
Alzheimer’s beta-amyloid protein. Int J Alzheimers Dis
2011, 304583.
Mezler M, Barghorn S, Schoemaker H, Gross G, Nimmrich V (2012) A beta-amyloid oligomer directly modulates
P/Q-type calcium currents in Xenopus oocytes. Br J Pharmacol 165, 1572-1583.
Chakroborty S, Kim J, Schneider C, Jacobson C, Molgo J,
Stutzmann GE (2012) Early presynaptic and postsynaptic
calcium signaling abnormalities mask underlying synaptic
depression in presymptomatic Alzheimer’s disease mice.
J Neurosci 32, 8341-8353.
Woods NK, Padmanabhan J (2012) Neuronal calcium signaling and Alzheimer’s disease. Adv Exp Med Biol 740,
1193-1217.
Lim YA, Giese M, Shepherd C, Halliday G, Kobayashi
M, Takamatsu K, Staufenbiel M, Eckert A, Gotz J (2012)
Role of hippocalcin in mediating Abeta toxicity. Biochim
Biophys Acta 1822, 1247-1257.
Chakroborty S, Stutzmann GE (2011) Early calcium
dysregulation in Alzheimer’s disease: Setting the stage
for synaptic dysfunction. Sci China Life Sci 54,
752-762.
Corona C, Pensalfini A, Frazzini V, Sensi SL (2011) New
therapeutic targets in Alzheimer’s disease: Brain deregulation of calcium and zinc. Cell Death Dis 2, e176.
Fedrizzi L, Carafoli E (2011) Ca2+ dysfunction in neurodegenerative disorders: Alzheimer’s disease. Biofactors
37, 189-196.
Yagami T, Kohma H, Yamamoto Y (2012) L-type voltagedependent calcium channels as therapeutic targets for
neurodegenerative diseases. Curr Med Chem 19, 48164827.
Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris
D (2011) Selective dihydropyiridine compounds facilitate the clearance of beta-amyloid across the blood-brain
barrier. Eur J Pharmacol 659, 124-129.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[123]
[124]
[125]
[126]
[127]
[128]
[129]
[130]
[131]
[132]
[133]
[134]
Paris D, Bachmeier C, Patel N, Quadros A, Volmar CH,
Laporte V, Ganey J, Beaulieu-Abdelahad D, it-Ghezala G,
Crawford F, Mullan MJ (2011) Selective antihypertensive
dihydropyridines lower Abeta accumulation by targeting
both the production and the clearance of Abeta across the
blood-brain barrier. Mol Med 17, 149-162.
Iwasaki K, Mishima K, Egashira N, Al-Khatib IH,
Ishibashi D, Irie K, Kobayashi H, Egawa T, Fujiwara
M (2003) Effect of nilvadipine on the cerebral ischemiainduced impairment of spatial memory and hippocampal
apoptosis in rats. J Pharmacol Sci 93, 188-196.
Iwasaki K, Egashira N, Takagaki Y, Yoshimitsu Y, HatipAl-Khatib I, Mishima K, Fujiwara M (2007) Nilvadipine
prevents the impairment of spatial memory induced by
cerebral ischemia combined with beta-amyloid in rats. Biol
Pharm Bull 30, 698-701.
Paris D, Quadros A, Humphrey J, Patel N, Crescentini
R, Crawford F, Mullan M (2004) Nilvadipine antagonizes both Abeta vasoactivity in isolated arteries, and the
reduced cerebral blood flow in APPsw transgenic mice.
Brain Res 999, 53-61.
Kennelly SP, Abdullah L, Paris D, Parish J, Mathura
V, Mullan M, Crawford F, Lawlor BA, Kenny RA
(2011) Demonstration of safety in Alzheimer’s patients
for intervention with an anti-hypertensive drug Nilvadipine: Results from a 6-week open label study. Int J Geriatr
Psychiatry 26, 1038-1045.
Kennelly S, Abdullah L, Kenny RA, Mathura V, Luis
CA, Mouzon B, Crawford F, Mullan M, Lawlor B (2012)
Apolipoprotein E genotype-specific short-term cognitive
benefits of treatment with the antihypertensive nilvadipine
in Alzheimer’s patients–an open-label trial. Int J Geriatr
Psychiatry 27, 415-422.
Hanyu H, Hirao K, Shimizu S, Iwamoto T, Koizumi K,
Abe K (2007) Favourable effects of nilvadipine on cognitive function and regional cerebral blood flow on SPECT
in hypertensive patients with mild cognitive impairment.
Nucl Med Commun 28, 281-287.
Hanyu H, Hirao K, Shimizu S, Sato T, Kiuchi A, Iwamoto
T (2007) Nilvadipine prevents cognitive decline of patients
with mild cognitive impairment. Int J Geriatr Psychiatry
22, 1264-1266.
Matsuda H, Araki N, Kuji I, Ohkubo T, Imabayashi E, Shimazu K (2008) Effect of nilvadipine on regional cerebral
blood flow in a patient with early Alzheimer disease. Clin
Nucl Med 33, 34-35.
Moriguchi S, Shioda N, Yamamoto Y, Tagashira H,
Fukunaga K (2012) The T-type voltage-gated calcium
channel as a molecular target of the novel cognitive
enhancer ST101: Enhancement of long-term potentiation
and CaMKII autophosphorylation in rat cortical slices. J
Neurochem 121, 44-53.
Yamaguchi Y, Miyashita H, Tsunekawa H, Mouri
A, Kim HC, Saito K, Matsuno T, Kawashima S,
Nabeshima T (2006) Effects of a novel cognitive enhancer, spiro[imidazo-[1,2-a]pyridine-3,2-indan]2(3H)-one (ZSET1446), on learning impairments induced
by amyloid-beta1-40 in the rat. J Pharmacol Exp Ther 317,
1079-1087.
Shioda N, Yamamoto Y, Han F, Moriguchi S, Yamaguchi
Y, Hino M, Fukunaga K (2010) A novel cognitive enhancer, ZSET1446/ST101, promotes hippocampal
neurogenesis and ameliorates depressive behavior in olfactory bulbectomized mice. J Pharmacol Exp Ther 333,
43-50.
[135]
[136]
[137]
[138]
[139]
[140]
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148]
[149]
[150]
59
Anekonda TS, Quinn JF, Harris C, Frahler K, Wadsworth
TL, Woltjer RL (2011) L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for
Alzheimer’s disease. Neurobiol Dis 41, 62-70.
Anekonda TS, Quinn JF (2011) Calcium channel blocking as a therapeutic strategy for Alzheimer’s disease: The
case for isradipine. Biochim Biophys Acta 1812, 15841590.
Copenhaver PF, Anekonda TS, Musashe D, Robinson KM,
Ramaker JM, Swanson TL, Wadsworth TL, Kretzschmar
D, Woltjer RL, Quinn JF (2011) A translational continuum
of model systems for evaluating treatment strategies in
Alzheimer’s disease: Isradipine as a candidate drug. Dis
Model Mech 4, 634-648.
Saletu B, Darragh A, Salmon P, Coen R (1989) EEG brain
mapping in evaluating the time-course of the central action
of DUP 996–a new acetylcholine releasing drug. Br J Clin
Pharmacol 28, 1-16.
van Dyck CH, Lin CH, Robinson R, Cellar J, Smith EO,
Nelson JC, Arnsten AF, Hoffer PB (1997) The acetylcholine releaser linopirdine increases parietal regional
cerebral blood flow in Alzheimer’s disease. Psychopharmacology (Berl) 132, 217-226.
Borjesson A, Karlsson T, Adolfsson R, Ronnlund M,
Nilsson L (1999) Linopirdine (DUP 996): Cholinergic
treatment of older adults using successive and nonsuccessive tests. Neuropsychobiology 40, 78-85.
Rose GM, Ong VS, Woodruff-Pak DS (2007) Efficacy of
MEM 1003, a novel calcium channel blocker, in delay
and trace eyeblink conditioning in older rabbits. Neurobiol
Aging 28, 766-773.
Denolle T, Sassano P, Allain H, tue-Ferrer D, Breton S,
Cimarosti I, Ouatara B, Merienne M, Gandon JM (2002)
Effects of nicardipine and clonidine on cognitive functions and electroencephalography in hypertensive patients.
Fundam Clin Pharmacol 16, 527-535.
Schwartz BL, Fay-McCarthy M, Kendrick K, Rosse RB,
Deutsch SI (1997) Effects of nifedipine, a calcium channel
antagonist, on cognitive function in schizophrenic patients
with tardive dyskinesia. Clin Neuropharmacol 20, 364370.
Ban TA, Morey L, Aguglia E, Azzarelli O, Balsano F,
Marigliano V, Caglieris N, Sterlicchio M, Capurso A,
Tomasi NA, (1990) Nimodipine in the treatment of old age
dementias. Prog Neuropsychopharmacol Biol Psychiatry
14, 525-551.
Izquierdo I (1990) Nimodipine and the recovery of memory. Trends Pharmacol Sci 11, 309-310.
Tedeschi D (1991) Calcium regulation in brain aging by
nimodipine: A multicenterctrial in Italy. Curr Ther Res 50,
553-563.
de Jonge MC, Traber J (1993) Nimodipine: Cognition,
aging, and degeneration. Clin Neuropharmacol 16(Suppl
1), S25-S30.
Fischhof PK (1993) Divergent neuroprotective effects of
nimodipine in PDD and MID provide indirect evidence of
disturbances in Ca2+ homeostasis in dementia. Methods
Find Exp Clin Pharmacol 15, 549-555.
Parnetti L, Senin U, Carosi M, Baasch H (1993) Mental
deterioration in old age: Results of two multicenter, clinical
trials with nimodipine. The Nimodipine Study Group. Clin
Ther 15, 394-406.
Bernhardt T, Kuebler J, Erzigkeit H (1995) Impairment
of cerebral function in old age: Nimodipine in general
practice. Eur J Clin Res 7, 205-215.
60
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
[163]
[164]
[165]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Fritze J, Walden J (1995) Clinical findings with nimodipine in dementia: Test of the calcium hypothesis. J Neural
Transm Suppl 46, 439-453.
Sze KH, Sim TC, Wong E, Cheng S, Woo J (1998) Effect
of nimodipine on memory after cerebral infarction. Acta
Neurol Scand 97, 386-392.
Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager
WH, Babarskiene MR, Babeanu S, Bossini A, GilExtremera B, Girerd X, Laks T, Lilov E, Moisseyev V,
TuomilehtoJ, Vanhanen H, Webster J, Yodfat Y, Fagard
R (1998) Prevention of dementia in randomised doubleblind placebo-controlled Systolic Hypertension in Europe
(Syst-Eur) trial. Lancet 352, 1347-1351.
Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR,
Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T,
Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster
J, Yodfat Y, Birkenhager WH (2002) The prevention of
dementia with antihypertensive treatment: New evidence
from the Systolic Hypertension in Europe (Syst-Eur) study.
Arch Intern Med 162, 2046-2052.
Valero T, del BL, Egea J, Canas N, Martinez A, Garcia
AG, Villarroya M, Lopez MG (2009) NP04634 prevents
cell damage caused by calcium overload and mitochondrial
disruption in bovine chromaffin cells. Eur J Pharmacol
607, 47-53.
O’Neill MJ, Bath CP, Dell CP, Hicks CA, Gilmore J,
Ambler SJ, Ward MA, Bleakman D (1997) Effects of Ca2+
and Na+ channel inhibitors in vitro and in global cerebral
ischaemia in vivo. Eur J Pharmacol 332, 121-131.
Paroczai M, Kiss B, Karpati E (1998) Effect of RGH-2716
on learning and memory deficits of young and aged rats in
water-labyrinth. Brain Res Bull 45, 475-488.
Fukumoto H, Kakihana M, Kaisho Y, Suno M (1997) The
novel compound TDN-345 induces synthesis/secretion of
nerve growth factor in C6-10A glioma cells. Brain Res
774, 87-93.
Nakayama T, Nagisa Y, Imamoto T, Nagai Y (1997) Beneficial effects of TDN-345, a novel Ca2+ antagonist, on
ischemic brain injury and cerebral glucose metabolism in
experimental animal models with cerebrovascular lesions.
Brain Res 762, 203-210.
Bourinet E, Stotz SC, Spaetgens RL, Dayanithi G, Lemos
J, Nargeot J, Zamponi GW (2001) Interaction of SNX482
with domains III and IV inhibits activation gating of
alpha(1E) (Ca(V)2.3) calcium channels. Biophys J 81,
79-88.
Kohlmeier KA, Leonard CS (2006) Transmitter modulation of spike-evoked calcium transients in arousal related
neurons: Muscarinic inhibition of SNX-482-sensitive calcium influx. Eur J Neurosci 23, 1151-1162.
Matthews EA, Bee LA, Stephens GJ, Dickenson AH
(2007) The Cav2.3 calcium channel antagonist SNX-482
reduces dorsal horn neuronal responses in a rat model
of chronic neuropathic pain. Eur J Neurosci 25, 35613569.
Miyake N, Wakamori M, Akaike N (1992) A new type
of Ca2+ channel blocker, NC-1100, inhibits the low- and
high-threshold Ca2+ currents in the rat CNS neurons.
Brain Res 598, 215-220.
Miyake N, Fujita R, Ishikawa M, Takayanagi M,
Takayanagi Y, Sasaki K (2000) Reversal of multidrug resistance in human leukemia K562 by tamolarizine, a novel
calcium antagonist. Jpn J Pharmacol 82, 265-268.
Tamura R, Nakada Y, Nishijo H, Miyake N, Ono T (2000)
Ameliorative effects of tamolarizine on place learning
[166]
[167]
[168]
[169]
[170]
[171]
[172]
[173]
[174]
[175]
[176]
[177]
[178]
[179]
[180]
[181]
impairment induced by transient forebrain ischemia in rats.
Brain Res 853, 81-92.
Zaczek R, Chorvat RJ, Saye JA, Pierdomenico ME,
Maciag CM, Logue AR, Fisher BN, Rominger DH,
Earl RA (1998) Two new potent neurotransmitter
release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)9(10H)-anthracenone: Comparison to linopirdine. J
Pharmacol Exp Ther 285, 724-730.
MacVinish LJ, Guo Y, Dixon AK, Murrell-Lagnado RD,
Cuthbert AW (2001) Xe991 reveals differences in K(+)
channels regulating chloride secretion in murine airway and colonic epithelium. Mol Pharmacol 60, 753760.
Schindowski K, Belarbi K, Buee L (2008) Neurotrophic
factors in Alzheimer’s disease: Role of axonal transport.
Genes Brain Behav 7(Suppl 1), 43-56.
Saragovi HU, Hamel E, Di PA (2009) A neurotrophic rationale for the therapy of neurodegenerative disorders. Curr
Alzheimer Res 6, 419-423.
Lu Y, Christian K, Lu B (2008) BDNF: A key regulator for
protein synthesis-dependent LTP and long-term memory?
Neurobiol Learn Mem 89, 312-323.
Nagahara AH, Tuszynski MH (2011) Potential therapeutic
uses of BDNF in neurological and psychiatric disorders.
Nat Rev Drug Discov 10, 209-219.
Fumagalli F, Racagni G, Riva MA (2006) The expanding role of BDNF: A therapeutic target for Alzheimer’s
disease? Pharmacogenomics J 6, 8-15.
Zhang F, Kang Z, Li W, Xiao Z, Zhou X (2012) Roles
of brain-derived neurotrophic factor/tropomyosin-related
kinase B (BDNF/TrkB) signalling in Alzheimer’s disease.
J Clin Neurosci 19, 946-949.
Castello NA, Green KN, Laferla FM (2012) Genetic
knockdown of brain-derived neurotrophic factor in 3xTgAD mice does not alter Abeta or tau pathology. PLoS One
7, e39566.
Capsoni S, Cattaneo A (2006) On the molecular basis linking nerve growth factor (NGF) to Alzheimer’s disease. Cell
Mol Neurobiol 26, 619-633.
Capsoni S, Tiveron C, Amato G, Vignone D, Cattaneo
A (2010) Peripheral neutralization of nerve growth factor
induces immunosympathectomy and central neurodegeneration in transgenic mice. J Alzheimers Dis 20, 527546.
Capsoni S, Brandi R, Arisi I, D’Onofrio M, Cattaneo A (2011) A dual mechanism linking NGF/proNGF
imbalance and early inflammation to Alzheimer’s disease
neurodegeneration in the AD11 anti-NGF mouse model.
CNS Neurol Disord Drug Targets 10, 635-647.
Cuello AC (2012) Gangliosides, NGF, brain aging and disease: A mini-review with personal reflections. Neurochem
Res 37, 1256-1260.
Cuello AC, Bruno MA, Bell KF (2007) NGF-cholinergic
dependency in brain aging, MCI and Alzheimer’s disease.
Curr Alzheimer Res 4, 351-358.
Cuello AC, Bruno MA, Allard S, Leon W, Iulita MF (2010)
Cholinergic involvement in Alzheimer’s disease. A link
with NGF maturation and degradation. J Mol Neurosci 40,
230-235.
Cuello AC, Ferretti MT, Iulita MF (2012) Preplaque (’preclinical’) Abeta-induced inflammation and nerve growth
factor deregulation in transgenic models of Alzheimer’s
disease-like amyloid pathology. Neurodegener Dis 10,
104-107.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[182]
[183]
[184]
[185]
[186]
[187]
[188]
[189]
[190]
[191]
[192]
[193]
[194]
Jonhagen ME (2000) Nerve growth factor treatment
in dementia. Alzheimer Dis Assoc Disord 14(Suppl 1),
S31-S38.
Cattaneo A, Calissano P (2012) Nerve growth factor and
Alzheimer’s disease: New facts for an old hypothesis. Mol
Neurobiol 46, 588-604.
Wang SH, Liao XM, Liu D, Hu J, Yin YY, Wang JZ, Zhu
LQ (2012) NGF promotes long-term memory formation
by activating poly(ADP-ribose)polymerase-1. Neuropharmacology 63, 1085-1092.
Bishop KM, Hofer EK, Mehta A, Ramirez A, Sun L,
Tuszynski M, Bartus RT (2008) Therapeutic potential of
CERE-110 (AAV2-NGF): Targeted, stable, and sustained
NGF delivery and trophic activity on rodent basal forebrain
cholinergic neurons. Exp Neurol 211, 574-584.
Mandel RJ (2010) CERE-110, an adeno-associated virusbased gene delivery vector expressing human nerve growth
factor for the treatment of Alzheimer’s disease. Curr Opin
Mol Ther 12, 240-247.
Jain P, Li R, Lama T, Saragovi HU, Cumberlidge G,
Meerovitch K (2011) An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and
demonstrates therapeutic efficacy in a rat model of dry
eye. Exp Eye Res 93, 503-512.
Visanji NP, Orsi A, Johnston TH, Howson PA, Dixon K,
Callizot N, Brotchie JM, Rees DD (2008) PYM50028, a
novel, orally active, nonpeptide neurotrophic factor inducer, prevents and reverses neuronal damage induced
by MPP+ in mesencephalic neurons and by MPTP in a
mouse model of Parkinson’s disease. FASEB J 22, 24882497.
Fukushima T, Nakamura A, Iwakami N, Nakada Y, Hattori H, Hoki S, Yamaguchi H, Nakagawa M, Terashima
N, Narita H (2011) T-817MA, a neuroprotective agent,
attenuates the motor and cognitive impairments associated
with neuronal degeneration in P301L tau transgenic mice.
Biochem Biophys Res Commun 407, 730-734.
Nguyen PT, Kimura T, Ho SA, Tran AH, Ono T, Nishijo H
(2007) Ameliorative effects of a neuroprotective agent, T817MA, on place learning deficits induced by continuous
infusion of amyloid-beta peptide (1-40) in rats. Hippocampus 17, 443-455.
Kimura T, Hong Nguyen PT, Ho SA, Tran AH, Ono T,
Nishijo H (2009) T-817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory
in rats infused i.c.v. with amyloid-beta peptide. Br J Pharmacol 157, 451-463.
Hirata K, Yamaguchi H, Takamura Y, Takagi A,
Fukushima T, Iwakami N, Saitoh A, Nakagawa M, Yamada
T (2005) A novel neurotrophic agent, T-817MA [1-{3[2-(1-benzothiophen-5-yl) ethoxy] propyl}-3-azetidinol
maleate], attenuates amyloid-beta-induced neurotoxicity
and promotes neurite outgrowth in rat cultured central nervous system neurons. J Pharmacol Exp Ther 314, 252-259.
Wahlberg LU, Lind G, Almqvist PM, Kusk P, Tornoe J, Juliusson B, Soderman M, Sellden E, Seiger A,
Eriksdotter-Jonhagen M, Linderoth B (2012) Targeted
delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: A technology platform for
restorative neurosurgery. J Neurosurg 117, 340-347.
Voutilainen MH, Back S, Porsti E, Toppinen L, Lindgren L, Lindholm P, Peranen J, Saarma M, Tuominen RK
(2009) Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson’s disease.
J Neurosci 29, 9651-9659.
[195]
[196]
[197]
[198]
[199]
[200]
[201]
[202]
[203]
[204]
[205]
[206]
[207]
[208]
[209]
61
Glembotski CC, Thuerauf DJ, Huang C, Vekich
JA, Gottlieb RA, Doroudgar S (2012) Mesencephalic
astrocyte-derived neurotrophic factor protects the heart
from ischemic damage and is selectively secreted upon
sarco/endoplasmic reticulum calcium depletion. J Biol
Chem 287, 25893-25904.
Devi L, Ohno M (2012) 7,8-dihydroxyflavone, a smallmolecule TrkB agonist, reverses memory deficits and
BACE1 elevation in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 37, 434-444.
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu
Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K (2010) A
selective TrkB agonist with potent neurotrophic activities
by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107,
2687-2692.
Johnson RA, Lam M, Punzo AM, Li H, Lin BR, Ye
K, Mitchell GS, Chang Q (2012) 7,8-dihydroxyflavone
exhibits therapeutic efficacy in a mouse model of Rett
syndrome. J Appl Physiol 112, 704-710.
Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K,
Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K (2010) A
synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect. J Med
Chem 53, 8274-8286.
Jang SW, Okada M, Sayeed I, Xiao G, Stein D, Jin P, Ye
K (2007) Gambogic amide, a selective agonist for TrkA
receptor that possesses robust neurotrophic activity, prevents neuronal cell death. Proc Natl Acad Sci U S A 104,
16329-16334.
Jang SW, Liu X, Chan CB, France SA, Sayeed I, Tang
W, Lin X, Xiao G, Andero R, Chang Q, Ressler KJ, Ye
K (2010) Deoxygedunin, a natural product with potent
neurotrophic activity in mice. PLoS One 5, e11528.
Nitta A, Ito M, Fukumitsu H, Ohmiya M, Ito H,
Sometani A, Nomoto H, Furukawa Y, Furukawa S (1999)
4-methylcatechol increases brain-derived neurotrophic
factor content and mRNA expression in cultured brain
cells and in rat brain in vivo. J Pharmacol Exp Ther 291,
1276-1283.
Sun MK, Alkon DL (2008) Effects of 4-methylcatechol on
spatial memory and depression. Neuroreport 19, 355-359.
Labie C, Canolle B, Chatelin S, Lafon C, Fournier J (2006)
Effects of paliroden (SR57667B) and xaliproden on adult
brain neurogenesis. Curr Alzheimer Res 3, 35-36.
Douillet P, Orgogozo JM (2009) What we have learned
from the Xaliproden Sanofi-aventis trials. J Nutr Health
Aging 13, 365-366.
Porzner M, Muller T, Seufferlein T (2009) SR 57746A/
xaliproden, a non-peptide neurotrophic compound:
Prospects and constraints for the treatment of nervous
system diseases. Expert Opin Investig Drugs 18, 17651772.
Mori T, Town T, TanJ, Yada N, Horikoshi Y, Yamamoto
J, Shimoda T, Kamanaka Y, Tateishi N, Asano T (2006)
Arundic Acid ameliorates cerebral amyloidosis and gliosis
in Alzheimer transgenic mice. J Pharmacol Exp Ther 318,
571-578.
Pettigrew LC, Kasner SE, Albers GW, Gorman M, Grotta
JC, Sherman DG, Funakoshi Y, Ishibashi H (2006) Safety
and tolerability of arundic acid in acute ischemic stroke. J
Neurol Sci 251, 50-56.
Pettigrew LC, Kasner SE, Gorman M, Atkinson RP,
Funakoshi Y, Ishibashi H (2006) Effect of arundic acid
on serum S-100beta in ischemic stroke. J Neurol Sci 251,
57-61.
62
[210]
[211]
[212]
[213]
[214]
[215]
[216]
[217]
[218]
[219]
[220]
[221]
[222]
[223]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Miyamoto Y, Nakahara M, Motoyama K, Ishiguro T,
Oda Y, Yamanoi T, Okamoto I, Yagi A, Nishimura H,
Hirayama F, Uekama K, Arima H (2011) Improvement of
some physicochemical properties of arundic acid, (R)-(-)2-propyloctanonic acid, by complexation with hydrophilic
cyclodextrins. Int J Pharm 413, 63-72.
Glasky AJ, Melchior CL, Pirzadeh B, Heydari N, Ritzmann RF (1994) Effect of AIT-082, a purine analog, on
working memory in normal and aged mice. Pharmacol
Biochem Behav 47, 325-329.
Glasky AJ, Glasky MS, Ritzmann RF, Rathbone MP
(1997) AIT-082, a novel purine derivative with neuroregenerative properties. Expert Opin Investig Drugs 6,
1413-1417.
Middlemiss PJ, Glasky AJ, Rathbone MP, Werstuik
E, Hindley S, Gysbers J (1995) AIT-082, a unique
purine derivative, enhances nerve growth factor mediated
neurite outgrowth from PC12 cells. Neurosci Lett 199,
131-134.
Rathbone MP, Middlemiss PJ, Crocker CE, Glasky MS,
Juurlink BH, Ramirez JJ, Ciccarelli R, Di IP, Caciagli F
(1999) AIT-082 as a potential neuroprotective and regenerative agent in stroke and central nervous system injury.
Expert Opin Investig Drugs 8, 1255-1262.
Lahiri DK, Ge YW, Farlow MR (2000) Effect of a memoryenhancing drug, AIT-082, on the level of synaptophysin.
Ann N Y Acad Sci 903, 387-393.
Taylor EM, Yan R, Hauptmann N, Maher TJ, Djahandideh
D, Glasky AJ (2000) AIT-082, a cognitive enhancer, is
transported into brain by a nonsaturable influx mechanism and out of brain by a saturable efflux mechanism.
J Pharmacol Exp Ther 293, 813-821.
Westlund KN, Lu Y, Werrbach-Perez K, Hulsebosch CE,
Morgan B, Pizzo DP, Eisenberg HM, Perez-Polo JR (1992)
Effects of nerve growth factor and acetyl-L-carnitine
arginyl amide on the human neuronal line HCN-1A. Int
J Dev Neurosci 10, 361-373.
Taglialatela G, Navarra D, Olivi A, Ramacci MT,
Werrbach-Perez K, Perez-Polo JR, Angelucci L (1995)
Neurite outgrowth in PC12 cells stimulated by acetyl-Lcarnitine arginine amide. Neurochem Res 20, 1-9.
Scorziello A, Meucci O, Calvani M, Schettini G
(1997) Acetyl-L-carnitine arginine amide prevents beta
25–35-induced neurotoxicity in cerebellar granule cells.
Neurochem Res 22, 257-265.
Ono S, Kitamura K, Maekawa M, Hirata K, Ano
M, Ukai W, Yamafuji T, Narita H (1993) Protective
effect of R(-)-1-(benzo[b]thiophen-5-yl)- 2-[2-(N,Ndiethylamino)ethoxy]ethanol hydrochloride (T-588), a
novel cerebral activator, against experimental cerebral
anoxia. Jpn J Pharmacol 62, 81-86.
Miyazaki H, Murayama T, Ono S, Narita H, Nomura
Y (1997) Effects of R(-)-1-(benzo[b]thiophen-5-yl)-2-[2N,N-diethylamino)ethoxy]ethan ol hydrochloride (T-588),
a novel cognitive enhancer, on noradrenaline release in
rat cerebral cortical slices. Biochem Pharmacol 53, 12631269.
Maekawa M, Murayama T, Ono S, Narita H, Nomura Y
(1998) The effects of T-588, a novel cognitive enhancer,
on noradrenaline uptake and release in rat cerebral cortical
slices. Jpn J Pharmacol 77, 155-160.
Iwasaki Y, Ikeda K, Ichikawa Y, Igarashi O, Kinoshita M,
Marubuchi S, Ono S (2002) T-588 enhances neurite outgrowth and choline acetyltransferase in cultured rat spinal
ventral horn neurons. Neurochem Res 27, 225-228.
[224]
[225]
[226]
[227]
[228]
[229]
[230]
[231]
[232]
[233]
[234]
[235]
[236]
[237]
[238]
[239]
[240]
Iwasaki Y, Ichikawa Y, Igarasi O, Aoyagi J, Konno S, Ikeda
K, Iguchi H, Kawabe S, Marubuchi S, Ono S (2003) T-588
protects motor neuron death against glutamate-induced
neurotoxicity. Neurochem Res 28, 1829-1832.
Iwasaki Y, Ichikawa Y, Igarashi O, Konno S, Aoyagi J,
Ikeda K, Marabuchi S, Ono S, Iguchi H, Kawabe K,
Fujioka T (2004) T-588 protects motor neuron death following axotomy. Neurochem Res 29, 403-406.
Yamamuro A, Ago Y, Maeda S, Sakai Y, Baba A, Matsuda
T (2003) Protective effect of T-588 on toxic damage by
serum deprivation and amyloid-beta protein in cultured
neurons. J Pharmacol Sci 92, 153-156.
Phuagphong P, Fukushima T, Hatanaka R, Tanaka K, Baba
A, Matsuda T (2004) T-588, a cognitive enhancer, protects
against sodium nitroprusside-induced toxicity in cultured
astrocytes. J Pharmacol Sci 95, 135-138.
Advokat C (2010) What are the cognitive effects
of stimulant medications? Emphasis on adults with
attention-deficit/hyperactivity disorder (ADHD). Neurosci
Biobehav Rev 34, 1256-1266.
Berridge CW, Devilbiss DM (2011) Psychostimulants
as cognitive enhancers: The prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder.
Biol Psychiatry 69, e101-e111.
Berridge CW, Shumsky JS, Andrzejewski ME, McGaughy
JA, Spencer RC, Devilbiss DM, Waterhouse BD (2012)
Differential sensitivity to psychostimulants across prefrontal cognitive tasks: Differential involvement of
noradrenergic alpha(1)- and alpha(2)-receptors. Biol Psychiatry 71, 467-473.
Dolder CR, Davis LN, McKinsey J (2010) Use of psychostimulants in patients with dementia. Ann Pharmacother 44,
1624-1632.
Arnsten AF, Pliszka SR (2011) Catecholamine influences
on prefrontal cortical function: Relevance to treatment of
attention deficit/hyperactivity disorder and related disorders. Pharmacol Biochem Behav 99, 211-216.
Bidwell LC, McClernon FJ, Kollins SH (2011) Cognitive enhancers for the treatment of ADHD. Pharmacol
Biochem Behav 99, 262-274.
Husain M, Mehta MA (2011) Cognitive enhancement by
drugs in health and disease. Trends Cogn Sci 15, 28-36.
Levin ED, Bushnell PJ, Rezvani AH (2011) Attentionmodulating effects of cognitive enhancers. Pharmacol
Biochem Behav 99, 146-154.
Sahakian BJ, Morein-Zamir S (2011) Neuroethical issues
in cognitive enhancement. J Psychopharmacol 25, 197204.
Ragan CI, Bard I, Singh I (2012) What should we do about
student use of cognitive enhancers? An analysis of current
evidence. Neuropharmacology 64, 588-595.
Wolkenberg SE, Sur C (2010) Recent progress in the discovery of non-sarcosine based GlyT1 inhibitors. Curr Top
Med Chem 10, 170-186.
Volkow ND, Wang GJ, Fowler JS, Ding YS (2005)
Imaging the effects of methylphenidate on brain
dopamine: New model on its therapeutic actions for
attention-deficit/hyperactivity disorder. Biol Psychiatry
57, 1410-1415.
Berridge CW, Devilbiss DM, Andrzejewski ME, Arnsten AF, Kelley AE, Schmeichel B, Hamilton C, Spencer
RC (2006) Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex
at low doses that enhance cognitive function. Biol Psychiatry 60, 1111-1120.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[241]
[242]
[243]
[244]
[245]
[246]
[247]
[248]
[249]
[250]
[251]
[252]
[253]
[254]
[255]
Devilbiss DM, Berridge CW (2008) Cognition-enhancing
doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry 64,
626-635.
Volkow ND, Fowler JS, Wang GJ, Telang F, Logan J, Wong
C, Ma J, Pradhan K, Benveniste H, Swanson JM (2008)
Methylphenidate decreased the amount of glucose needed
by the brain to perform a cognitive task. PLoS One 3,
e2017.
Repantis D, Schlattmann P, Laisney O, Heuser I (2010)
Modafinil and methylphenidate for neuroenhancement in
healthy individuals: A systematic review. Pharmacol Res
62, 187-206.
Prashad M, Kim HY, Lu Y, Liu Y, Har D, Repic O,
Blacklock TJ, Giannousis P (1999) The First Enantioselective Synthesis of (2R,2’R)-threo-(+)-Methylphenidate
Hydrochloride. J Org Chem 64, 1750-1753.
Spencer TJ, Bonab AA, Dougherty DD, Mirto T, Martin J,
Clarke A, Fischman AJ (2012) Understanding the central
pharmacokinetics of spheroidal oral drug absorption system (SODAS) dexmethylphenidate: A positron emission
tomography study of dopamine transporter receptor occupancy measured with C-11 altropane. J Clin Psychiatry
73, 346-352.
Schmitt KC, Reith ME (2011) The atypical stimulant and
nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like
inhibitors. PLoS One 6, e25790.
Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ
(2004) Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol
Psychiatry 55, 1031-1040.
Turner DC, Clark L, Pomarol-Clotet E, McKenna P,
Robbins TW, Sahakian BJ (2004) Modafinil improves
cognition and attentional set shifting in patients with
chronic schizophrenia. Neuropsychopharmacology 29,
1363-1373.
Scoriels L, Barnett JH, Murray GK, Cherukuru S, Fielding M, Cheng F, Lennox BR, Sahakian BJ, Jones PB
(2011) Effects of modafinil on emotional processing in
first episode psychosis. Biol Psychiatry 69, 457-464.
Scoriels L, Barnett JH, Soma PK, Sahakian BJ, Jones PB
(2012) Effects of modafinil on cognitive functions in first
episode psychosis. Psychopharmacology (Berl) 220, 249258.
Scoriels L, Jones PB, Sahakian BJ (2013) Modafinil effects
on cognition and emotion in schizophrenia and its neurochemical modulation in the brain. Neuropharmacology 64,
168-184.
Rasetti R, Mattay VS, Stankevich B, Skjei K, Blasi G,
Sambataro F, rrillaga-Romany IC, Goldberg TE, Callicott JH, Apud JA, Weinberger DR (2010) Modulatory
effects of modafinil on neural circuits regulating emotion and cognition. Neuropsychopharmacology 35, 21012109.
Muller U, Rowe JB, Rittman T, Lewis C, Robbins TW,
Sahakian BJ (2013) Effects of modafinil on non-verbal
cognition, task enjoyment and creative thinking in healthy
volunteers. Neuropharmacology 64, 490-495.
Brady KT, Gray KM, Tolliver BK (2011) Cognitive
enhancers in the treatment of substance use disorders: Clinical evidence. Pharmacol Biochem Behav 99, 285-294.
Kalechstein AD, Mahoney JJ III, Yoon JH, Bennett R, De
La GR (2013) Modafinil, but not escitalopram, improves
working memory and sustained attention in long-term,
[256]
[257]
[258]
[259]
[260]
[261]
[262]
[263]
[264]
[265]
[266]
[267]
63
high-dose cocaine users. Neuropharmacology 64, 472478.
Sutherland SM, Adler LA, Chen C, Smith MD, Feltner
DE (2012) An 8-week, randomized controlled trial of atomoxetine, atomoxetine plus buspirone, or placebo in adults
with ADHD. J Clin Psychiatry 73, 445-450.
Gehlert DR, Schober DA, Hemrick-Luecke SK, Krushinski J, Howbert JJ, Robertson DW, Fuller RW, Wong DT
(1995) Novel halogenated analogs of tomoxetine that are
potent and selective inhibitors of norepinephrine uptake in
brain. Neurochem Int 26, 47-52.
Chamberlain SR, Del CN, Dowson J, Muller U, Clark
L, Robbins TW, Sahakian BJ (2007) Atomoxetine
improved response inhibition in adults with attention
deficit/hyperactivity disorder. Biol Psychiatry 62, 977-984.
Chamberlain SR, Hampshire A, Muller U, Rubia K, Del
CN, Craig K, Regenthal R, Suckling J, Roiser JP, Grant
JE, Bullmore ET, Robbins TW, Sahakian BJ (2009) Atomoxetine modulates right inferior frontal activation during
inhibitory control: A pharmacological functional magnetic
resonance imaging study. Biol Psychiatry 65, 550-555.
Wigal SB, Wong AA, Jun A, Stehli A, SteinbergEpstein R, Lerner MA (2012) Adverse events in
medication treatment-naive children with attentiondeficit/hyperactivity disorder: Results from a small,
controlled trial of lisdexamfetamine dimesylate. J Child
Adolesc Psychopharmacol 22, 149-156.
Rothman RB, Baumann MH, Dersch CM, Romero DV,
Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type
central nervous system stimulants release norepinephrine
more potently than they release dopamine and serotonin.
Synapse 39, 32-41.
Kojima T, Niigata K, Fujikura T, Tachikawa S,
Nozaki Y, Kagami S, Takahashi K (1985) Syntheses
of (+/-)-2-[(inden-7-yloxy)methyl]morpholine hydrochloride (YM-08054, indeloxazine hydrochloride) and its
derivatives with potential cerebral-activating and antidepressive properties. Chem Pharm Bull (Tokyo) 33,
3766-3774.
Yamamoto M, Ooyama M, Ozawa Y, Okada M, Tada
S, Yamaguchi T, Endo H (1993) Effects of indeloxazine
hydrochloride, a cerebral activator, on passive avoidance
learning impaired by disruption of cholinergic transmission in rats. Neuropharmacology 32, 695-701.
Yamamoto M, Takahashi K, Ohyama M, Sasamata M, Yatsugi S, Okada M, Endoh H (1994) Possible involvement
of central cholinergic system in ameliorating effects of
indeloxazine, a cerebral activator, on disturbance of learning behavior in rats. Prog Neuropsychopharmacol Biol
Psychiatry 18, 603-613.
Yamaguchi T, Ozawa Y, Suzuki M, Yamamoto M, Nakamura T, Yamaura A (1996) Indeloxazine hydrochloride
improves impairment of passive avoidance performance
after fluid percussion brain injury in rats. Neuropharmacology 35, 329-336.
Yamaguchi T, Suzuki M, Yamamoto M (1997) Facilitation of acetylcholine release in rat frontal cortex by
indeloxazine hydrochloride: Involvement of endogenous
serotonin and 5-HT4 receptors. Naunyn Schmiedebergs
Arch Pharmacol 356, 712-720.
Yamaguchi T, Ohyama M, Suzuki M, Ozawa Y, Hatanaka
K, Hidaka K, Yamamoto M (1998) Neurochemical and
behavioral characterization of potential antidepressant
properties of indeloxazine hydrochloride. Neuropharmacology 37, 1169-1176.
64
[268]
[269]
[270]
[271]
[272]
[273]
[274]
[275]
[276]
[277]
[278]
[279]
[280]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Kurosawa Y, Degrauw TJ, Lindquist DM, Blanco VM,
Pyne-Geithman GJ, Daikoku T, Chambers JB, Benoit SC,
Clark JF (2012) Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. J Clin
Invest 122, 2837-2846.
Sugane T, Tobe T, Hamaguchi W, Shimada I, Maeno
K, Miyata J, Suzuki T, Kimizuka T, Kohara A, Morita
T, Doihara H, Saita K, Aota M, Furutani M, Shimada Y, Hamada N, Sakamoto S, Tsukamoto S (2011)
Synthesis and biological evaluation of 3-biphenyl-4-yl-4phenyl-4H-1,2,4-triazoles as novel glycine transporter 1
inhibitors. J Med Chem 54, 387-391.
Sugane T, Tobe T, Hamaguchi W, Shimada I, Maeno K,
Miyata J, Suzuki T, Kimizuka T, Morita T, Sakamoto S,
Tsukamoto S (2012) Synthesis and biological evaluation
of (4H-1,2,4-triazol-4-yl)isoquinoline derivatives as selective glycine transporter 1 inhibitors. Bioorg Med Chem 20,
34-41.
Erdo SL, Kiss B, Rosdy B (1981) Inhibition of dopamine
uptake by a new psychostimulant mesocarb (Sydnocarb).
Pol J Pharmacol Pharm 33, 141-147.
Ganiev MM, Kharlamov AN, Raevskii KS, Guseinov DI
(1987) Effect of sidnocarb on learning and memory. Biull
Eksp Biol Med 104, 453-454.
Schmeichel BE, Zemlan FP, Berridge CW (2013) A
selective dopamine reuptake inhibitor improves prefrontal
cortex-dependent cognitive function: Potential relevance
to attention deficit hyperactivity disorder. Neuropharmacology 64, 321-328.
Nic Dhonnchadha BA, Kantak KM (2011) Cognitive
enhancers for facilitating drug cue extinction: Insights
from animal models. Pharmacol Biochem Behav 99,
229-244.
Nic Dhonnchadha BA, Pinard E, Alberati D, Wettstein
JG, Spealman RD, Kantak KM (2012) Inhibiting glycine
transporter-1 facilitates cocaine-cue extinction and attenuates reacquisition of cocaine-seeking behavior. Drug
Alcohol Depend 122, 119-126.
Chow TW, Pollock BG, Milgram NW (2007) Potential
cognitive enhancing and disease modification effects of
SSRIs for Alzheimer’s disease. Neuropsychiatr Dis Treat
3, 627-636.
Cassano GB, Puca F, Scapicchio PL, Trabucchi M (2002)
Paroxetine and fluoxetine effects on mood and cognitive
functions in depressed nondemented elderly patients. J
Clin Psychiatry 63, 396-402.
Pollock BG, Mulsant BH, Rosen J, Sweet RA, Mazumdar S, Bharucha A, Marin R, Jacob NJ, Huber KA,
Kastango KB, Chew ML (2002) Comparison of citalopram, perphenazine, and placebo for the acute treatment
of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry 159, 460465.
Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J,
Steffen J, Schumacher T, Bruning T, Plath AS, Alfen F,
Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J,
Walker LC, Pahnke J (2011) Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein
ABCC1 in mice. J Clin Invest 121, 3924-3931.
Harada K, Nakato K, Yarimizu J, Yamazaki M, Morita M,
Takahashi S, Aota M, Saita K, Doihara H, Sato Y, Yamaji
T, Ni K, Matsuoka N (2012) A novel glycine transporter-1
(GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazol e),
improves cognition in animal models of cognitive impair-
[281]
[282]
[283]
[284]
[285]
[286]
[287]
[288]
[289]
[290]
[291]
[292]
ment in schizophrenia and Alzheimer’s disease. Eur J
Pharmacol 685, 59-69.
Murai S, Saito H, Abe E, Masuda Y, Odashima J, Itoh
T (1994) MKC-231, a choline uptake enhancer, ameliorates working memory deficits and decreased hippocampal
acetylcholine induced by ethylcholine aziridinium ion in
mice. J Neural Transm Gen Sect 98, 1-13.
Bessho T, Takashina K, Tabata R, Ohshima C, Chaki H,
Yamabe H, Egawa M, Tobe A, Saito K (1996) Effect
of the novel high affinity choline uptake enhancer 2-(2oxopyrrolidin-1-yl)-N-(2,3-dimethyl-5,6,7,8- tetrahydrofuro [2,3-b] quinolin-4-yl)acetoamide on deficits of water
maze learning in rats. Arzneimittelforschung 46, 369373.
Bessho T, Takashina K, Eguchi J, Komatsu T, Saito
K (2008) MKC-231, a choline-uptake enhancer: (1)
long-lasting cognitive improvement after repeated administration in AF64A-treated rats. J Neural Transm 115,
1019-1025.
Takashina K, Bessho T, Mori R, Eguchi J, Saito K (2008)
MKC-231, a choline uptake enhancer: (2) Effect on synthesis and release of acetylcholine in AF64A-treated rats.
J Neural Transm 115, 1027-1035.
Takashina K, Bessho T, Mori R, Kawai K, Eguchi J, Saito
K (2008) MKC-231, a choline uptake enhancer: (3) Mode
of action of MKC-231 in the enhancement of high-affinity
choline uptake. J Neural Transm 115, 1037-1046.
Akaike A, Maeda T, Kaneko S, Tamura Y (1998) Protective
effect of MKC-231, a novel high affinity choline uptake
enhancer, on glutamate cytotoxicity in cultured cortical
neurons. Jpn J Pharmacol 76, 219-222.
Uemura K, Yoshioka S, Surina-Baumgartner DM, Tamagawa T, Miura H, Ueda M, Tamaya N, Iguchi A, Hotta N
(1999) Central nervous system-mediated hyperglycemic
effects of NIK-247, a cholinesterase inhibitor, and MKC231, a choline uptake enhancer, in rats. Jpn J Pharmacol
79, 113-115.
Shirayama Y, Yamamoto A, Nishimura T, Katayama S,
Kawahara R (2007) Subsequent exposure to the choline
uptake enhancer MKC-231 antagonizes phencyclidineinduced behavioral deficits and reduction in septal
cholinergic neurons in rats. Eur Neuropsychopharmacol
17, 616-626.
Shimazaki T, Kaku A, Chaki S (2010) D-Serine and a
glycine transporter-1 inhibitor enhance social memory in
rats. Psychopharmacology (Berl) 209, 263-270.
Boulay D, Pichat P, Dargazanli G, Estenne-Bouhtou G,
Terranova JP, Rogacki N, Stemmelin J, Coste A, Lanneau
C, Desvignes C, Cohen C, Alonso R, Vige X, Biton B,
Steinberg R, Sevrin M, Oury-Donat F, George P, Bergis
O, Griebel G, Avenet P, Scatton B (2008) Characterization of SSR103800, a selective inhibitor of the glycine
transporter-1 in models predictive of therapeutic activity
in schizophrenia. Pharmacol Biochem Behav 91, 47-58.
Boulay D, Bergis O, Avenet P, Griebel G (2010) The
glycine transporter-1 inhibitor SSR103800 displays a
selective and specific antipsychotic-like profile in normal
and transgenic mice. Neuropsychopharmacology 35, 416427.
Black MD, Varty GB, Arad M, Barak S, De LA, Boulay
D, Pichat P, Griebel G, Weiner I (2009) Procognitive and
antipsychotic efficacy of glycine transport 1 inhibitors
(GlyT1) in acute and neurodevelopmental models of
schizophrenia: Latent inhibition studies in the rat. Psychopharmacology (Berl) 202, 385-396.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[293]
[294]
[295]
[296]
[297]
[298]
[299]
[300]
[301]
[302]
[303]
[304]
[305]
[306]
[307]
Depoortere R, Dargazanli G, Estenne-Bouhtou G, Coste
A, Lanneau C, Desvignes C, Poncelet M, Heaulme M,
Santucci V, Decobert M, Cudennec A, Voltz C, Boulay D,
Terranova JP, StemmelinJ, Roger P, Marabout B, Sevrin
M, Vige X, Biton B, Steinberg R, Francon D, Alonso R,
Avenet P, Oury-Donat F, Perrault G, Griebel G, George
P, Soubrie P, Scatton B (2005) Neurochemical, electrophysiological and pharmacological profiles of the selective
inhibitor of the glycine transporter-1 SSR504734, a potential new type of antipsychotic. Neuropsychopharmacology
30, 1963-1985.
Singer P, Feldon J, Yee BK (2009) The glycine transporter
1 inhibitor SSR504734 enhances working memory performance in a continuous delayed alternation task in C57BL/6
mice. Psychopharmacology (Berl) 202, 371-384.
Singer P, Feldon J, Yee BK (2009) Interactions between
the glycine transporter 1(GlyT1) inhibitor SSR504734 and
psychoactive drugs in mouse motor behaviour. Eur Neuropsychopharmacol 19, 571-580.
Nishikawa H, Inoue T, Izumi T, Nakagawa S, Koyama
T (2010) SSR504734, a glycine transporter-1 inhibitor,
attenuates acquisition and expression of contextual conditioned fear in rats. Behav Pharmacol 21, 576-579.
Nikiforuk A, Kos T, Rafa D, Behl B, Bespalov A, Popik P
(2011) Blockade of glycine transporter 1 by SSR-504734
promotes cognitive flexibility in glycine/NMDA receptordependent manner. Neuropharmacology 61, 262-267.
(1999) Sufoxazine. Lucelan, Metatone, teniloxazine, Y
8894. Drugs R D 2, 66-67.
Anami K, Yamamoto Y, Setoguchi M (1985) Pharmacological studies on sufoxazine (Y-8894). (I) Effects on
experimental amnesia in mice. Nihon Yakurigaku Zasshi
85, 71-77.
Anami K, Yamamoto Y, Setoguchi M, Maruyama Y (1987)
Pharmacological studies on Y-8894. (V) Effect on learning
and memory in intact and experimentally amnesic rats.
Nihon Yakurigaku Zasshi 89, 145-153.
Anami K, Setoguchi M, Senoh H (1988) Pharmacological
studies on Y-8894. (VIII). Effects on learning and memory
in the radial maze task in mice. Nihon Yakurigaku Zasshi
92, 113-118.
Lehr T, Staab A, Trommeshauser D, Schaefer HG,
Kloft C (2010) Quantitative pharmacology approach in
Alzheimer’s disease: Efficacy modeling of early clinical
data to predict clinical outcome of tesofensine. AAPS J
12, 117-129.
van de Giessen E, de Bruin K, la Fleur SE, van den Brink
W, Booij J (2012) Triple monoamine inhibitor tesofensine
decreases food intake, body weight, and striatal dopamine
D2/D3 receptor availability in diet-induced obese rats. Eur
Neuropsychopharmacol 22, 290-299.
Adam Y, Edwards RH, Schuldiner S (2008) Expression
and function of the rat vesicular monoamine transporter.
Am J Physiol Cell Physiol 294, C1004-C1011.
Koeppe RA, Gilman S, Joshi A, Liu S, Little R, Junck
L, Heumann M, Frey KA, Albin RL (2005) 11C-DTBZ
and 18F-FDG PET measures in differentiating dementias.
J Nucl Med 46, 936-944.
Gilman S, Koeppe RA, Little R, An H, Junck L, Giordani
B, Persad C, Heumann M, Wernette K (2004) Striatal monoamine terminals in Lewy body dementia and
Alzheimer’s disease. Ann Neurol 55, 774-780.
Koeppe RA, Gilman S, Junck L, Wernette K, Frey KA
(2008) Differentiating Alzheimer’s disease from dementia with Lewy bodies and Parkinson’s disease with
[308]
[309]
[310]
[311]
[312]
[313]
[314]
[315]
[316]
[317]
[318]
[319]
[320]
65
(+)-[11C]dihydrotetrabenazine positron emission tomography. Alzheimers Dement 4, S67-S76.
Nagren K, Halldin C, Rinne JO (2010) Radiopharmaceuticals for positron emission tomography investigations of
Alzheimer’s disease. Eur J Nucl Med Mol Imaging 37,
1575-1593.
Zhu L, Liu Y, Plossl K, Lieberman B, Liu J, Kung HF
(2010) An improved radiosynthesis of [18F]AV-133: A
PET imaging agent for vesicular monoamine transporter
2. Nucl Med Biol 37, 133-141.
Tsao HH, Lin KJ, Juang JH, Skovronsky DM, Yen TC,
Wey SP, Kung MP (2010) Binding characteristics of 9fluoropropyl-(+)-dihydrotetrabenzazine (AV-133) to the
vesicular monoamine transporter type 2 in rats. Nucl Med
Biol 37, 413-419.
Wang JL, Oya S, Parhi AK, Lieberman BP, Ploessl K,
Hou C, Kung HF (2010) In vivo studies of the SERTselective [18F]FPBM and VMAT2-selective [18F]AV-133
radiotracers in a rat model of Parkinson’s disease. Nucl
Med Biol 37, 479-486.
Lin KJ, Weng YH, Wey SP, Hsiao IT, Lu CS, Skovronsky D, Chang HP, Kung MP, Yen TC (2010) Whole-body
biodistribution and radiation dosimetry of 18F-FP-(+)DTBZ (18F-AV-133): A novel vesicular monoamine
transporter 2 imaging agent. J Nucl Med 51, 14801485.
Okamura N, Villemagne VL, Drago J, Pejoska S, Dhamija
RK, Mulligan RS, Ellis JR, Ackermann U, O’Keefe G,
Jones G, Kung HF, Pontecorvo MJ, Skovronsky D, Rowe
CC (2010) In vivo measurement of vesicular monoamine
transporter type 2 density in Parkinson disease with (18)FAV-133. J Nucl Med 51, 223-228.
Villemagne VL, Okamura N, Pejoska S, Drago J, Mulligan
RS, Chetelat G, Ackermann U, O’Keefe G, Jones G, Gong
S, Tochon-Danguy H, Kung HF, Masters CL, Skovronsky DM, Rowe CC (2011) In vivo assessment of vesicular
monoamine transporter type 2 in dementia with lewy bodies and Alzheimer disease. Arch Neurol 68, 905-912.
Lin KJ, Lin WY, Hsieh CJ, Weng YH, Wey SP, Lu CS,
Skovronsky D, Yen TC, Chang CJ, Kung MP, Hsiao IT
(2011) Optimal scanning time window for 18F-FP-(+)DTBZ (18F-AV-133) summed uptake measurements. Nucl
Med Biol 38, 1149-1155.
Toomey JS, Bhatia S, Moon LT, Orchard EA, Tainter KH,
Lokitz SJ, Terry T, Mathis JM, Penman AD (2012) PET
imaging a MPTP-induced mouse model of Parkinson’s disease using the fluoropropyl-dihydrotetrabenazine analog
[(18)F]-DTBZ (AV-133). PLoS One 7, e39041.
Rinne JO, Sahlberg N, Ruottinen H, Nagren K, Lehikoinen
P (1998) Striatal uptake of the dopamine reuptake ligand
[11C]beta-CFT is reduced in Alzheimer’s disease assessed
by positron emission tomography. Neurology 50, 152-156.
Rinne JO, Bergman J, Ruottinen H, Haaparanta M, Eronen
E, Oikonen V, Sonninen P, Solin O (1999) Striatal uptake
of a novel PET ligand, [18F]beta-CFT, is reduced in early
Parkinson’s disease. Synapse 31, 119-124.
Rinne JO, Nagren K (2010) Positron emission tomography
in at risk patients and in the progression of mild cognitive
impairment to Alzheimer’s disease. J Alzheimers Dis 19,
291-300.
McKeith I, O’Brien J, Walker Z, Tatsch K, Booij J, Darcourt J, Padovani A, Giubbini R, Bonuccelli U, Volterrani
D, Holmes C, Kemp P, Tabet N, Meyer I, Reininger C
(2007) Sensitivity and specificity of dopamine transporter
imaging with 123I-FP-CIT SPECT in dementia with Lewy
66
[321]
[322]
[323]
[324]
[325]
[326]
[327]
[328]
[329]
[330]
[331]
[332]
[333]
[334]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
bodies: A phase III, multicentre study. Lancet Neurol 6,
305-313.
Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince PG, Perry R, McKeith I, Katona CL
(2007) Dementia with Lewy bodies: A comparison of clinical diagnosis, FP-CIT single photon emission computed
tomography imaging and autopsy. J Neurol Neurosurg
Psychiatry 78, 1176-1181.
Vlaar AM, de NT, Kessels AG, Vreeling FW, Winogrodzka
A, Mess WH, Tromp SC, van Kroonenburgh MJ, Weber
WE (2008) Diagnostic value of 123I-ioflupane and
123I-iodobenzamide SPECT scans in 248 patients with
parkinsonian syndromes. Eur Neurol 59, 258-266.
Roselli F, Pisciotta NM, Perneczky R, Pennelli M, Aniello
MS, De Caro MF, Ferrannini E, Tartaglione B, Defazio
G, Rubini G, Livrea P (2009) Severity of neuropsychiatric
symptoms and dopamine transporter levels in dementia
with Lewy bodies: A 123I-FP-CIT SPECT study. Mov
Disord 24, 2097-2103.
Roselli F, Pisciotta NM, Pennelli M, Aniello MS, Gigante
A, De Caro MF, Ferrannini E, Tartaglione B, NiccoliAsabella A, Defazio G, Livrea P, Rubini G (2010)
Midbrain SERT in degenerative parkinsonisms: A 123IFP-CIT SPECT study. Mov Disord 25, 1853-1859.
Gerasimou G, Costa DC, Papanastasiou E, Bostanjiopoulou S, Arnaoutoglou M, Moralidis E, Aggelopoulou
T, Gotzamani-Psarrakou A (2012) SPECT study with
I-123-Ioflupane (DaTSCAN) in patients with essential
tremor. Is there any correlation with Parkinson’s disease?
Ann Nucl Med 26, 337-344.
Scott R, Bourtchuladze R, Gossweiler S, Dubnau J, Tully
T (2002) CREB and the discovery of cognitive enhancers.
J Mol Neurosci 19, 171-177.
Saura CA, Valero J (2011) The role of CREB signaling
in Alzheimer’s disease and other cognitive disorders. Rev
Neurosci 22, 153-169.
Saura CA (2012) CREB-regulated transcription coactivator 1-dependent transcription in Alzheimer’s disease mice.
Neurodegener Dis 10, 250-252.
Scott Bitner R (2012) Cyclic AMP response elementbinding protein (CREB) phosphorylation: A mechanistic
marker in the development of memory enhancing
Alzheimer’s disease therapeutics. Biochem Pharmacol 83,
705-714.
Oliveira AM, Bading H (2011) Calcium signaling in cognition and aging-dependent cognitive decline. Biofactors
37, 168-174.
Espana J, Valero J, Minano-Molina AJ, Masgrau R, Martin E, Guardia-Laguarta C, Lleo A, Gimenez-Llort L,
Rodriguez-Alvarez J, Saura CA (2010) beta-Amyloid disrupts activity-dependent gene transcription required for
memory through the CREB coactivator CRTC1. J Neurosci
30, 9402-9410.
Helm KA, Haberman RP, Dean SL, Hoyt EC, Melcher T,
Lund PK, Gallagher M (2005) GABAB receptor antagonist SGS742 improves spatial memory and reduces protein
binding to the cAMP response element (CRE) in the hippocampus. Neuropharmacology 48, 956-964.
Florian C, Mons N, Roullet P (2006) CREB antisense
oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long- but not short-term
spatial memory in mice. Learn Mem 13, 465-472.
Fontan-Lozano A, Romero-Granados R, del-Pozo-Martin
Y, Suarez-Pereira I, gado-Garcia JM, Penninger JM, Carrion AM (2009) Lack of DREAM protein enhances
[335]
[336]
[337]
[338]
[339]
[340]
[341]
[342]
[343]
[344]
[345]
[346]
[347]
[348]
[349]
[350]
[351]
learning and memory and slows brain aging. Curr Biol
19, 54-60.
Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A,
Van NW, Miano JM, Zlokovic BV (2007) Serum response
factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer’s
phenotype. Proc Natl Acad Sci U S A 104, 823828.
Bell RD (2012) The imbalance of vascular molecules in
Alzheimer’s disease. J Alzheimers Dis 32, 699-709.
McPhee I, Gibson LC, Kewney J, Darroch C, Stevens
PA, Spinks D, Cooreman A, Mackenzie SJ (2005) Cyclic
nucleotide signalling: A molecular approach to drug discovery for Alzheimer’s disease. Biochem Soc Trans 33,
1330-1332.
Reddy PH, Beal MF (2008) Amyloid beta, mitochondrial
dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol
Med 14, 45-53.
Di Bona D, Scapagnini G, Candore G, Castiglia L,
Colonna-Romano G, Duro G, Nuzzo D, Iemolo F, Lio
D, Pellicano M, Scafidi V, Caruso C, Vasto S (2010)
Immune-inflammatory responses and oxidative stress
in Alzheimer’s disease: Therapeutic implications. Curr
Pharm Des 16, 684-691.
Obrenovich ME, Li Y, Parvathaneni K, Yendluri BB, Palacios HH, Leszek J, Aliev G (2011) Antioxidants in health,
disease and aging. CNS Neurol Disord Drug Targets 10,
192-207.
Pratico D (2008) Oxidative stress hypothesis in
Alzheimer’s disease: A reappraisal. Trends Pharmacol Sci
29, 609-615.
Pratico D (2008) Evidence of oxidative stress in
Alzheimer’s disease brain and antioxidant therapy: Lights
and shadows. Ann N Y Acad Sci 1147, 70-78.
Young KJ, Bennett JP (2010) The mitochondrial
secret(ase) of Alzheimer’s disease. J Alzheimers Dis
20(Suppl 2), S381-S400.
Halliwell B (1999) Antioxidant defence mechanisms:
From the beginning to the end (of the beginning). Free
Radic Res 31, 261-272.
Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant
treatment. Drugs Aging 18, 685-716.
Halliwell B (2006) Oxidative stress and neurodegeneration: Where are we now? J Neurochem 97, 1634-1658.
Halliwell B (2011) Free radicals and antioxidants - quo
vadis? Trends Pharmacol Sci 32, 125-130.
Lee HP, Zhu X, Casadesus G, Castellani RJ, Nunomura
A, Smith MA, Lee HG, Perry G (2010) Antioxidant
approaches for the treatment of Alzheimer’s disease.
Expert Rev Neurother 10, 1201-1208.
Vina J, Lloret A, Giraldo E, Badia MC, Alonso MD (2011)
Antioxidant pathways in Alzheimer’s disease: Possibilities
of intervention. Curr Pharm Des 17, 3861-3864.
Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J,
Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok
H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY,
Chan MH, Szeto S, Chan IH, Mok V (2008) Six-month
randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J
Clin Psychopharmacol 28, 110-113.
Halliwell B (1999) Vitamin C: Poison, prophylactic or
panacea? Trends Biochem Sci 24, 255-259.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[352]
[353]
[354]
[355]
[356]
[357]
[358]
[359]
[360]
[361]
[362]
[363]
[364]
[365]
[366]
[367]
[368]
[369]
Lloret A, Badia MC, Mora NJ, Pallardo FV, Alonso MD,
Vina J (2009) Vitamin E paradox in Alzheimer’s disease:
It does not prevent loss of cognition and may even be
detrimental. J Alzheimers Dis 17, 143-149.
Brewer GJ (2010) Why vitamin E therapy fails for treatment of Alzheimer’s disease. J Alzheimers Dis 19, 27-30.
Usoro OB, Mousa SA (2010) Vitamin E forms in
Alzheimer’s disease: A review of controversial and clinical
experiences. Crit Rev Food Sci Nutr 50, 414-419.
Guan JZ, Guan WP, Maeda T, Makino N (2012) Effect
of vitamin E administration on the elevated oxygen stress
and the telomeric and subtelomeric status in Alzheimer’s
disease. Gerontology 58, 62-69.
Behl C (1999) Alzheimer’s disease and oxidative stress:
Implications for novel therapeutic approaches. Prog Neurobiol 57, 301-323.
Behl C (2005) Oxidative stress in Alzheimer’s disease:
Implications for prevention and therapy. Subcell Biochem
38, 65-78.
Aliev G, Smith MA, Seyidov D, Neal ML, Lamb BT,
Nunomura A, Gasimov EK, Vinters HV, Perry G, Lamanna
JC, Friedland RP (2002) The role of oxidative stress in the
pathophysiology of cerebrovascular lesions in Alzheimer’s
disease. Brain Pathol 12, 21-35.
Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G (2008)
Antioxidant therapy in Alzheimer’s disease: Theory and
practice. Mini Rev Med Chem 8, 1395-1406.
Aliev G, Palacios HH, Walrafen B, Lipsitt AE, Obrenovich ME, Morales L (2009) Brain mitochondria as a
primary target in the development of treatment strategies
for Alzheimer disease. Int J Biochem Cell Biol 41, 19892004.
Moreira PI, Honda K, Liu Q, Aliev G, Oliveira CR, Santos MS, Zhu X, Smith MA, Perry G (2005) Alzheimer’s
disease and oxidative stress: The old problem remains
unsolved. Curr Med Chem Central Nervous System Agents
5, 51-62.
Moreira PI, Santos MS, Oliveira CR (2007) Alzheimer’s
disease: A lesson from mitochondrial dysfunction.
Antioxid Redox Signal 9, 1621-1630.
Chauhan V, Chauhan A (2006) Oxidative stress in
Alzheimer’s disease. Pathophysiology 13, 195-208.
Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry
G, Smith MA (2006) Involvement of oxidative stress in
Alzheimer disease. J Neuropathol Exp Neurol 65, 631641.
Nunomura A, Moreira PI, Lee HG, Zhu X, Castellani RJ, Smith MA, Perry G (2007) Neuronal death
and survival under oxidative stress in Alzheimer and
Parkinson diseases. CNS Neurol Disord Drug Targets 6,
411-423.
Onyango IG, Khan SM (2006) Oxidative stress, mitochondrial dysfunction, and stress signaling in Alzheimer’s
disease. Curr Alzheimer Res 3, 339-349.
Liu Q, Xie F, Rolston R, Moreira PI, Nunomura A, Zhu
X, Smith MA, Perry G (2007) Prevention and treatment of
Alzheimer disease and aging: Antioxidants. Mini Rev Med
Chem 7, 171-180.
Kamat CD, Gadal S, Mhatre M, Williamson KS, Pye QN,
Hensley K (2008) Antioxidants in central nervous system
diseases: Preclinical promise and translational challenges.
J Alzheimers Dis 15, 473-493.
Toogood PL (2008) Mitochondrial drugs. Curr Opin Chem
Biol 12, 457-463.
[370]
[371]
[372]
[373]
[374]
[375]
[376]
[377]
[378]
[379]
[380]
[381]
[382]
[383]
[384]
[385]
[386]
67
Shen L, Ji HF (2010) Insights into the disappointing clinical trials of antioxidants in neurodegenerative diseases. J
Alzheimers Dis 19, 1141-1142.
Mecocci P, Polidori MC (2012) Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease.
Biochim Biophys Acta 1822, 631-638.
Pocernich CB, Butterfield DA (2012) Elevation of glutathione as a therapeutic strategy in Alzheimer disease.
Biochim Biophys Acta 1822, 625-630.
Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine
TJ, Thomas RG, Aisen P (2012) Antioxidants for
Alzheimer disease: A randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69, 836841.
Kitagawa Y (2006) Edaravone in acute ischemic stroke.
Intern Med 45, 225-226.
Tsujita K, Shimomura H, Kaikita K, Kawano H, Hokamaki
J, Nagayoshi Y, Yamashita T, Fukuda M, Nakamura Y,
Sakamoto T, Yoshimura M, Ogawa H (2006) Long-term
efficacy of edaravone in patients with acute myocardial
infarction. Circ J 70, 832-837.
Lapchak PA (2010) A critical assessment of edaravone
acute ischemic stroke efficacy trials: Is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother
11, 1753-1763.
Kikuchi K, Kawahara K, Miyagi N, Uchikado H,
Kuramoto T, Morimoto Y, Tancharoen S, Miura N, Takenouchi K, Oyama Y, Shrestha B, Matsuda F, Yoshida Y,
Arimura S, Mera K, Tada K, Yoshinaga N, Maenosono
R, Ohno Y, Hashiguchi T, Maruyama I, Shigemori M
(2010) Edaravone: A new therapeutic approach for the
treatment of acute stroke. Med Hypotheses 75, 583585.
Gillis JC, Benefield P, McTavish D (1994) Idebenone.
A review of its pharmacodynamic and pharmacokinetic
properties, and therapeutic use in age-related cognitive
disorders. Drugs Aging 5, 133-152.
Weyer G, Babej-Dolle RM, Hadler D, Hofmann S, Herrmann WM (1997) A controlled study of 2 doses of
idebenone in the treatment of Alzheimer’s disease. Neuropsychobiology 36, 73-82.
Voronkova KV, Meleshkov MN (2009) Use of Noben
(idebenone) in the treatment of dementia and memory
impairments without dementia. Neurosci Behav Physiol
39, 501-506.
Haley EC Jr (1998) High-dose tirilazad for acute stroke
(RANTTAS II). RANTTAS II Investigators. Stroke 29,
1256-1257.
Dorsch NW, Kassell NF, Sinkula MS (2001) Metaanalysis
of trials of tirilazad mesylate in aneurysmal SAH. Acta
Neurochir Suppl 77, 233-235.
Kavanagh RJ, Kam PC (2001) Lazaroids: Efficacy and
mechanism of action of the 21-aminosteroids in neuroprotection. Br J Anaesth 86, 110-119.
Jang YG, Ilodigwe D, Macdonald RL (2009) Metaanalysis
of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care 10, 141-147.
Kelso GF, Porteous CM, Hughes G, Ledgerwood EC, Gane
AM, Smith RA, Murphy MP (2002) Prevention of mitochondrial oxidative damage using targeted antioxidants.
Ann N Y Acad Sci 959, 263-274.
Murphy MP, Smith RA (2007) Targeting antioxidants to
mitochondria by conjugation to lipophilic cations. Annu
Rev Pharmacol Toxicol 47, 629-656.
68
[387]
[388]
[389]
[390]
[391]
[392]
[393]
[394]
[395]
[396]
[397]
[398]
[399]
[400]
[401]
[402]
[403]
[404]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Smith RA, Murphy MP (2010) Animal and human studies
with the mitochondria-targeted antioxidant MitoQ. Ann N
Y Acad Sci 1201, 96-103.
Smith RA, Murphy MP (2011) Mitochondria-targeted
antioxidants as therapies. Discov Med 11, 106-114.
Reddy PH (2008) Mitochondrial medicine for aging and
neurodegenerative diseases. Neuromolecular Med 10, 291315.
Reddy PH, Reddy TP (2011) Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr
Alzheimer Res 8, 393-409.
Reddy PH, Tripathi R, Troung Q, Tirumala K, Reddy TP,
Anekonda V, Shirendeb UP, Calkins MJ, Reddy AP, Mao
P, Manczak M (2011) Abnormal mitochondrial dynamics
and synaptic degeneration as early events in Alzheimer’s
disease: Implications to mitochondria-targeted antioxidant
therapeutics. Biochim Biophys Acta 1822, 639-649.
Bonda DJ, Wang X, Gustaw-Rothenberg KA, Perry
G, Smith MA, Zhu X (2009) Mitochondrial drugs for
Alzheimer disease. Pharmaceuticals (Basel) 2, 287-298.
Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M,
Zhu X, Smith MA (2010) Oxidative stress in Alzheimer
disease: A possibility for prevention. Neuropharmacology
59, 290-294.
Manczak M, Mao P, Calkins MJ, Cornea A, Reddy
AP, Murphy MP, Szeto HH, Park B, Reddy PH
(2010) Mitochondria-targeted antioxidants protect against
amyloid-beta toxicity in Alzheimer’s disease neurons. J
Alzheimers Dis 20(Suppl 2), S609-S631.
Smith RA, Porteous CM, Coulter CV, Murphy MP (1999)
Selective targeting of an antioxidant to mitochondria. Eur
J Biochem 263, 709-716.
Reddy PH (2006) Mitochondrial oxidative damage in
aging and Alzheimer’s disease: Implications for mitochondrially targeted antioxidant therapeutics. J Biomed
Biotechnol 2006, 31372.
Kotake Y (1999) Pharmacologic properties of phenyl Ntert-butylnitrone. Antioxid Redox Signal 1, 481-499.
Lin S, Rhodes PG, Lei M, Zhang F, Cai Z (2004) alphaPhenyl-n-tert-butyl-nitrone attenuates hypoxic-ischemic
white matter injury in the neonatal rat brain. Brain Res
1007, 132-141.
Robertson L, Hartley RC (2009) Synthesis of Narylpyridinium salts bearing a nitrone spin trap as
potential mitochondria-targeted antioxidants. Tetrahedron
65, 5284-5292.
Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller
PW, Szeto HH (2004) Cell-permeable peptide antioxidants
targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion
injury. J Biol Chem 279, 34682-34690.
Reddy PH (2007) Mitochondrial dysfunction in aging
and Alzheimer’s disease: Strategies to protect neurons.
Antioxid Redox Signal 9, 1647-1658.
Rocha M, Hernandez-Mijares A, Garcia-Malpartida K,
Banuls C, Bellod L, Victor VM (2010) Mitochondriatargeted antioxidant peptides. Curr Pharm Des 16,
3124-3131.
Szeto HH, Schiller PW (2011) Novel therapies targeting
inner mitochondrial membrane–from discovery to clinical
development. Pharm Res 28, 2669-2679.
Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione
B, Ghiso J, Pappolla MA (1999) Potent neuroprotective properties against the Alzheimer beta-amyloid
by an endogenous melatonin-related indole structure,
[405]
[406]
[407]
[408]
[409]
[410]
[411]
[412]
[413]
[414]
[415]
[416]
[417]
[418]
indole-3-propionic acid. J Biol Chem 274, 2193721942.
Liang LP, Huang J, Fulton R, Day BJ, Patel M (2007) An
orally active catalytic metalloporphyrin protects against 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity
in vivo. J Neurosci 27, 4326-4333.
Liang LP, Waldbaum S, Rowley S, Huang TT, Day BJ,
Patel M (2012) Mitochondrial oxidative stress and epilepsy
in SOD2 deficient mice: Attenuation by a lipophilic metalloporphyrin. Neurobiol Dis 45, 1068-1076.
Day BJ, Patel M (2008) Metalloporphyrin catalytic antioxidants for the potential treatment of neurodegenerative
diseases. Drugs Future 33, 1025-1032.
Batinic-Haberle I, Reboucas JS, Spasojevic I (2010)
Superoxide dismutase mimics: Chemistry, pharmacology,
and therapeutic potential. Antioxid Redox Signal 13, 877918.
Batinic-Haberle I, Rajic Z, Tovmasyan A, Reboucas JS,
Ye X, Leong KW, Dewhirst MW, Vujaskovic Z, Benov L,
Spasojevic I (2011) Diverse functions of cationic Mn(III)
N-substituted pyridylporphyrins, recognized as SOD mimics. Free Radic Biol Med 51, 1035-1053.
Sheng H, Batinc-Haberle I, Warner DS (2002) Catalytic
antioxidants as novel pharmacologic approaches to treatment of ischemic brain injury. Drug News Perspect 15,
654-665.
Sheng H, Yang W, Fukuda S, Tse HM, Paschen W, Johnson
K, Batinic-Haberle I, Crapo JD, Pearlstein RD, Piganelli
J, Warner DS (2009) Long-term neuroprotection from a
potent redox-modulating metalloporphyrin in the rat. Free
Radic Biol Med 47, 917-923.
Sheng H, Spasojevic I, Tse HM, Jung JY, Hong J,
Zhang Z, Piganelli JD, Batinic-Haberle I, Warner
DS (2011) Neuroprotective efficacy from a lipophilic
redox-modulating Mn(III) N-Hexylpyridylporphyrin,
MnTnHex-2-PyP: Rodent models of ischemic stroke and
subarachnoid hemorrhage. J Pharmacol Exp Ther 338,
906-916.
Li L, Zhang B, Tao Y, Wang Y, Wei H, Zhao J, Huang R, Pei
Z (2009) DL-3-n-butylphthalide protects endothelial cells
against oxidative/nitrosative stress, mitochondrial damage
and subsequent cell death after oxygen glucose deprivation
in vitro. Brain Res 1290, 91-101.
Xiong N, Huang J, Chen C, Zhao Y, Zhang Z, Jia M, Zhang
Z, Hou L, Yang H, Cao X, Liang Z, Zhang Y, Sun S, Lin
Z, Wang T (2012) Dl-3-n-butylphthalide, a natural antioxidant, protects dopamine neurons in rotenone models for
Parkinson’s disease. Neurobiol Aging 33, 1777-1791.
Valgimigli L, Valgimigli M, Gaiani S, Pedulli GF, Bolondi
L (2000) Measurement of oxidative stress in human liver
by EPR spin-probe technique. Free Radic Res 33, 167-178.
D’Aleo V, Del GS, Martano M, Bonamassa B, Canistro
D, Soleti A, Valgimigli L, Paolini M, Filipponi F, Boggi
U, Del PS, Lupi R (2009) The non-peptidyl low molecular
weight radical scavenger IAC protects human pancreatic
islets from lipotoxicity. Mol Cell Endocrinol 309, 63-66.
Vasina V, Broccoli M, Ursino MG, Bellot SF, Soleti A,
Paolini M, De PF (2009) Effects of the non-peptidyl low
molecular weight radical scavenger IAC in DNBS-induced
colitis in rats. Eur J Pharmacol 614, 137-145.
Vasina V, Broccoli M, Ursino MG, Canistro D, Valgimigli
L, Soleti A, Paolini M, De PF (2010) Non-peptidyl low
molecular weight radical scavenger IAC attenuates DSSinduced colitis in rats. World J Gastroenterol 16, 36423650.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[419]
[420]
[421]
[422]
[423]
[424]
[425]
[426]
[427]
[428]
[429]
[430]
[431]
Puolivali J, Nurmi A, Miettinen TK, Soleti A, Riccardino
F, Kalesnykas G, Heikkinen T, Vartiainen N, Pussinen
R, Tahtivaara L, Lehtimaki K, Yrjanheikki J, Canistro
D, Sapone A, Spisni E, Paolini M (2011) The radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4piperidinyl) decantionate) decreases mortality, enhances
cognitive functions in water maze and reduces amyloid
plaque burden in hAbetaPP transgenic mice. J Alzheimers
Dis 27, 499-510.
Giles FJ, Fracasso PM, Kantarjian HM, Cortes JE, Brown
RA, Verstovsek S, Alvarado Y, Thomas DA, Faderl S,
Garcia-Manero G, Wright LP, Samson T, Cahill A, Lambert P, Plunkett W, Sznol M, DiPersio JF, Gandhi V
(2003) Phase I and pharmacodynamic study of Triapine, a
novel ribonucleotide reductase inhibitor, in patients with
advanced leukemia. Leuk Res 27, 1077-1083.
Chen RW, Yao C, Lu XC, Jiang ZG, Whipple R, Liao Z,
Ghanbari HA, Almassian B, Tortella FC, Dave JR (2005)
PAN-811 (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), a novel neuroprotectant, elicits its function in
primary neuronal cultures by up-regulating Bcl-2 expression. Neuroscience 135, 191-201.
Gao X, Zheng CY, Qin GW, Tang XC, Zhang HY
(2012) S-52, a novel nootropic compound, protects against
beta-amyloid induced neuronal injury by attenuating
mitochondrial dysfunction. J Neurosci Res 90, 19811988.
Zhong SZ, Ge QH, Li Q, Qu R, Ma SP (2009) Peoniflorin
attentuates Abeta((1-42))-mediated neurotoxicity by regulating calcium homeostasis and ameliorating oxidative
stress in hippocampus of rats. J Neurol Sci 280, 71-78.
Hatanaka M, Nishizawa C, Kakinoki T, Takahashi K,
Nakamura S, Mashino T (2008) 2,2 -Pyridoin derivatives
protect HL-60 cells against oxidative stress. Bioorg Med
Chem Lett 18, 5290-5293.
Xu H, Wang H, Zhuang L, Yan B, Yu Y, Wei Z, Zhang Y,
Dyck LE, Richardson SJ, He J, Li X, Kong J, Li XM (2008)
Demonstration of an anti-oxidative stress mechanism of
quetiapine: Implications for the treatment of Alzheimer’s
disease. FEBS J 275, 3718-3728.
Han M, Liu Y, Tan Q, Zhang B, Wang W, Liu J, Zhang
XJ, Wang YY, Zhang JM (2011) Therapeutic efficacy
of stemazole in a beta-amyloid injection rat model of
Alzheimer’s disease. Eur J Pharmacol 657, 104-110.
Choi SJ, Jeong CH, Choi SG, Chun JY, Kim YJ, Lee J,
Shin DH, Heo HJ (2009) Zeatin prevents amyloid betainduced neurotoxicity and scopolamine-induced cognitive
deficits. J Med Food 12, 271-277.
Flaherty DP, Kiyota T, Dong Y, Ikezu T, Vennerstrom JL
(2010) Phenolic bis-styrylbenzenes as beta-amyloid binding ligands and free radical scavengers. J Med Chem 53,
7992-7999.
Lenhart JA, Ling X, Gandhi R, Guo TL, Gerk PM, Brunzell
DH, Zhang S (2010) “Clicked” bivalent ligands containing curcumin and cholesterol as multifunctional abeta
oligomerization inhibitors: Design, synthesis, and biological characterization. J Med Chem 53, 6198-6209.
Jung YS, Kang TS, Yoon JH, Joe BY, Lim HJ, Seong CM,
Park WK, Kong JY, Cho J, Park NS (2002) Synthesis and
evaluation of 4-hydroxyphenylacetic acid amides and 4hydroxycinnamamides as antioxidants. Bioorg Med Chem
Lett 12, 2599-2602.
Weston RM, Jarrott B, Ishizuka Y, Callaway JK (2006)
AM-36 modulates the neutrophil inflammatory response
and reduces breakdown of the blood brain barrier after
[432]
[433]
[434]
[435]
[436]
[437]
[438]
[439]
[440]
[441]
[442]
[443]
[444]
[445]
[446]
69
endothelin-1 induced focal brain ischaemia. Br J Pharmacol 149, 712-723.
Nicolazzo JA, Nguyen TT, Katneni K, Steuten JA,
Smith G, Jarrott B, Callaway JK, Charman SA (2008)
Pharmacokinetics and brain uptake of AM-36, a novel neuroprotective agent, following intravenous administration to
rats. J Pharm Pharmacol 60, 171-178.
Sorbera LA, Leeson PA, Castaner J (2001) CPI-1189.
Drugs Future 26, 647-650.
Clifford DB, McArthur JC, Schifitto G, Kieburtz K,
McDermott MP, Letendre S, Cohen BA, Marder K, Ellis
RJ, Marra CM (2002) A randomized clinical trial of CPI1189 for HIV-associated cognitive-motor impairment.
Neurology 59, 1568-1573.
Strid S, Borga O, Edenius C, Jostell KG, Odergren T, Weil
A (2002) Pharmacokinetics in renally impaired subjects
of NXY-059, a nitrone-based, free-radical trapping agent
developed for the treatment of acute stroke. Eur J Clin
Pharmacol 58, 409-415.
Green AR, Shuaib A (2006) Therapeutic strategies for the
treatment of stroke. Drug Discov Today 11, 681-693.
Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM,
Diener HC, Grotta J, Lyden P, Shuaib A, Hardemark
HG, Wasiewski WW (2006) NXY-059 for acute ischemic
stroke. N Engl J Med 354, 588-600.
Lees KR, Davalos A, Davis SM, Diener HC, Grotta
J, Lyden P, Shuaib A, Ashwood T, Hardemark HG,
Wasiewski W, Emeribe U, Zivin JA (2006) Additional
outcomes and subgroup analyses of NXY-059 for acute
ischemic stroke in the SAINT I trial. Stroke 37, 2970-2978.
Ginsberg MD (2007) Life after cerovive: A personal perspective on ischemic neuroprotection in the post-NXY-059
era. Stroke 38, 1967-1972.
Lyden PD, Shuaib A, Lees KR, Davalos A, Davis SM,
Diener HC, Grotta JC, Ashwood TJ, Hardemark HG,
Svensson HH, Rodichok L, Wasiewski WW, Ahlberg
G (2007) Safety and tolerability of NXY-059 for acute
intracerebral hemorrhage: The CHANT Trial. Stroke 38,
2262-2269.
Saver JL (2007) Clinical impact of NXY-059 demonstrated
in the SAINT I trial: Derivation of number needed to treat
for benefit over entire range of functional disability. Stroke
38, 1515-1518.
Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis
SM, Diener HC, Ashwood T, Wasiewski WW, Emeribe
U (2007) NXY-059 for the treatment of acute ischemic
stroke. N Engl J Med 357, 562-571.
Cheng YF, Jiang J, Hu P, Reinholdsson I, Guo W, Asenblad N, Nilsson D (2008) Pharmacokinetics of 8-hour
intravenous infusion of NXY-059: A phase I, randomized,
double-blind (within dose panels), placebo-controlled
study in healthy Chinese volunteers. Clin Ther 30, 23422353.
Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, Davis
SM, Shuaib A, Ashwood T, Wasiewski W, Alderfer V,
Hardemark HG, Rodichok L (2008) NXY-059 for the treatment of acute stroke: Pooled analysis of the SAINT I and
II Trials. Stroke 39, 1751-1758.
Savitz SI, Schabitz WR (2008) A Critique of SAINT II:
Wishful thinking, dashed hopes, and the future of neuroprotection for acute stroke. Stroke 39, 1389-1391.
Iwashita A, Maemoto T, Nakada H, Shima I, Matsuoka N, Hisajima H (2003) A novel potent radical scavenger, 8-(4-fluorophenyl)-2-((2E)-3-phenyl-2propenoyl)-1,2,3,4-tetrahydropyrazol o[5,1-c] [1,2,4]tri-
70
[447]
[448]
[449]
[450]
[451]
[452]
[453]
[454]
[455]
[456]
[457]
[458]
[459]
[460]
[461]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
azine (FR210575), prevents neuronal cell death in cultured
primary neurons and attenuates brain injury after focal
ischemia in rats. J Pharmacol Exp Ther 307, 961-968.
Dage JL, Ackermann BL, Barbuch RJ, Bernotas RC,
Ohlweiler DF, Haegele KD, Thomas CE (1997) Evidence
for a novel pentyl radical adduct of the cyclic nitrone spin
trap MDL 101,002. Free Radic Biol Med 22, 807-812.
Johnson MP, McCarty DR, Velayo NL, Markgraf CG,
Chmielewski PA, Ficorilli JV, Cheng HC, Thomas CE
(1998) MDL 101,002, a free radical spin trap, is efficacious in permanent and transient focal ischemia models.
Life Sci 63, 241-253.
Galeano M, Torre V, Deodato B, Campo GM, Colonna M,
Sturiale A, Squadrito F, Cavallari V, Cucinotta D, Buemi
M, Altavilla D (2001) Raxofelast, a hydrophilic vitamin Elike antioxidant, stimulates wound healing in genetically
diabetic mice. Surgery 129, 467-477.
Altavilla D, Galeano M, Bitto A, Minutoli L, Squadrito
G, Seminara P, Venuti FS, Torre V, Calo M, Colonna
M, Lo CP, Giugliano G, Scuderi N, Mioni C, Leone
S, Squadrito F (2005) Lipid peroxidation inhibition by
raxofelast improves angiogenesis and wound healing in
experimental burn wounds. Shock 24, 85-91.
Altavilla D, Marini H, Seminara P, Squadrito G, Minutoli L, Passaniti M, Bitto A, Calapai G, Calo M, Caputi
AP, Squadrito F (2005) Protective effects of antioxidant
raxofelast in alcohol-induced liver disease in mice. Pharmacology 74, 6-14.
Bitto A, Minutoli L, Squadrito F, Polito F, Altavilla D
(2007) Raxofelast, (+/–)5-(acetyloxy)-2,3-dihydro-4,6,7trimethyl-2-benzofuranacetic acid: A new antioxidant to
modulate the inflammatory response during ischemiareperfusion injury and impaired wound healing. Mini Rev
Med Chem 7, 339-343.
Dorrell S (2001) Alzheimer’s disease - a metallic problem.
Drug Discov Today 6, 61-62.
Perry G, Cash AD, Srinivas R, Smith MA (2002) Metals
and oxidative homeostasis in Alzheimer’s disease. Drug
Dev Res 56, 293-299.
Bush AI (2003) The metallobiology of Alzheimer’s disease. Trends Neurosci 26, 207-214.
Crouch PJ, Barnham KJ, Bush AI, White AR (2006) Therapeutic treatments for Alzheimer’s disease based on metal
bioavailability. Drug News Perspect 19, 469-474.
Schugar H, Green DE, Bowen ML, Scott LE, Storr
T, Bohmerle K, Thomas F, Allen DD, Lockman PR,
Merkel M, Thompson KH, Orvig C (2007) Combating Alzheimer’s disease with multifunctional molecules
designed for metal passivation. Angew Chem Int Ed Engl
46, 1716-1718.
Shcherbatykh I, Carpenter DO (2007) The role of metals
in the etiology of Alzheimer’s disease. J Alzheimers Dis
11, 191-205.
Storr T, Merkel M, Song-Zhao GX, Scott LE, Green DE,
Bowen ML, Thompson KH, Patrick BO, Schugar HJ,
Orvig C (2007) Synthesis, characterization, and metal
coordinating ability of multifunctional carbohydratecontaining compounds for Alzheimer’s therapy. J Am
Chem Soc 129, 7453-7463.
Barnham KJ, Bush AI (2008) Metals in Alzheimer’s and
Parkinson’s diseases. Curr Opin Chem Biol 12, 222-228.
Bush AI (2008) Drug development based on the metals
hypothesis of Alzheimer’s disease. J Alzheimers Dis 15,
223-240.
[462]
[463]
[464]
[465]
[466]
[467]
[468]
[469]
[470]
[471]
[472]
[473]
[474]
[475]
[476]
[477]
Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer’s
disease based on the metal hypothesis. Neurotherapeutics
5, 421-432.
Bolognin S, Messori L, Zatta P (2009) Metal ion
physiopathology in neurodegenerative disorders. Neuromolecular Med 11, 223-238.
Bolognin S, Drago D, Messori L, Zatta P (2009) Chelation
therapy for neurodegenerative diseases. Med Res Rev 29,
547-570.
Rodriguez-Rodriguez C, Sanchez de GN, Rimola A,
Avarez-Larena A, Lloveras V, Vidal-Gancedo J, Ventura S,
Vendrell J, Sodupe M, Gonzalez-Duarte P (2009) Design,
selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for
application in Alzheimer’s disease. J Am Chem Soc 131,
1436-1451.
Storr T, Scott LE, Bowen ML, Green DE, Thompson KH,
Schugar HJ, Orvig C (2009) Glycosylated tetrahydrosalens
as multifunctional molecules for Alzheimer’s therapy. Dalton Trans, 3034-3043.
Zatta P, Drago D, Bolognin S, Sensi SL (2009) Alzheimer’s
disease, metal ions and metal homeostatic therapy. Trends
Pharmacol Sci 30, 346-355.
Bandyopadhyay S, Huang X, Lahiri DK, Rogers JT (2010)
Novel drug targets based on metallobiology of Alzheimer’s
disease. Expert Opin Ther Targets 14, 1177-1197.
Choi JS, Braymer JJ, Nanga RP, Ramamoorthy A, Lim
MH (2010) Design of small molecules that target metalA{beta} species and regulate metal-induced A{beta}
aggregation and neurotoxicity. Proc Natl Acad Sci U S
A 107, 21990-21995.
Braymer JJ, DeToma AS, Choi JS, Ko KS, Lim MH (2010)
Recent development of bifunctional small molecules to
study metal-amyloid-beta species in Alzheimer’s disease.
Int J Alzheimers Dis 2011, 623051.
Duce JA, Bush AI (2010) Biological metals and
Alzheimer’s disease: Implications for therapeutics and
diagnostics. Prog Neurobiol 92, 1-18.
Rodriguez-Rodriguez C, Rimola A, Rodriguez-Santiago
L, Ugliengo P, Avarez-Larena A, Gutierrez-de-Teran H,
Sodupe M, Gonzalez-Duarte P (2010) Crystal structure
of thioflavin-T and its binding to amyloid fibrils: Insights
at the molecular level. Chem Commun (Camb) 46, 11561158.
Braymer JJ, Choi JS, DeToma AS, Wang C, Nam K,
Kampf JW, Ramamoorthy A, Lim MH (2011) Development of bifunctional stilbene derivatives for targeting and
modulating metal-amyloid-beta species. Inorg Chem 50,
10724-10734.
Choi JS, Braymer JJ, Park SK, Mustafa S, Chae J, Lim MH
(2011) Synthesis and characterization of IMPY derivatives
that regulate metal-induced amyloid-beta aggregation.
Metallomics 3, 284-291.
Rimola A, Ali-Torres J, Rodriguez-Rodriguez C, Poater
J, Matito E, Sola M, Sodupe M (2011) Ab initio design
of chelating ligands relevant to Alzheimer’s disease:
Influence of metalloaromaticity. J Phys Chem A 115,
12659-12666.
Kenche VB, Barnham KJ (2011) Alzheimer’s disease &
metals: Therapeutic opportunities. Br J Pharmacol 163,
211-219.
Tomljenovic L (2011) Aluminum and Alzheimer’s disease:
After a century of controversy, is there a plausible link?
J Alzheimers Dis 23, 567-598.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[478]
[479]
[480]
[481]
[482]
[483]
[484]
[485]
[486]
[487]
[488]
[489]
[490]
[491]
[492]
[493]
[494]
Manso Y, Comes G, Hidalgo J, Bush AI, Adlard PA (2011)
Copper modulation as a therapy for Alzheimer’s disease?
Int J Alzheimers Dis 2011, 370345.
Crouch PJ, Barnham KJ (2012) Therapeutic redistribution
of metal ions to treat Alzheimer’s disease. Acc Chem Res
45, 1604-1611.
Grasso G, Giuffrida ML, Rizzarelli E (2012) Metallostasis
and amyloid beta-degrading enzymes. Metallomics 4, 937949.
Hung LW, Barnham KJ (2012) Modulating metals as a
therapeutic strategy for Alzheimer’s disease. Future Med
Chem 4, 955-969.
Squitti R (2012) Metals in Alzheimer’s disease: A systemic
perspective. Front Biosci 17, 451-472.
Watt AD, Villemagne VL, Barnham KJ (2012) Metals,
membranes, and amyloid-beta oligomers: Key pieces in
the Alzheimer’s disease puzzle? J Alzheimers Dis, doi:
10.3233/JAD-2012-129017 [Epub ahead of print].
Craddock TJ, Tuszynski JA, Chopra D, Casey N, Goldstein
LE, Hameroff SR, Tanzi RE (2012) The zinc dyshomeostasis hypoothesis of Alzheimer’s disease. PloS ONE, 7,
3.
Wise-Scira O, Xu L, Perry G, Coskuner O (2012) Structures and free energy landscapes of aqueous zinc(II)-bound
amyloid-beta(1-40) and zinc(II)-bound amyloid-beta(142) with dynamics. J Biol Inorg Chem 17, 927-938.
Rosenberg G, Angel I, Kozak A (2005) Clinical
pharmacology of DP-b99 in healthy volunteers: First
administration to humans. Br J Clin Pharmacol 60, 7-16.
Diener HC, Schneider D, Lampl Y, Bornstein NM, Kozak
A, Rosenberg G (2008) DP-b99, a membrane-activated
metal ion chelator, as neuroprotective therapy in ischemic
stroke. Stroke 39, 1774-1778.
Rosenberg G, Bornstein N, Diener HC, Gorelick PB,
Shuaib A, Lees K (2011) The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in acute
ischemic stroke: A randomized, double-blind, placebocontrolled, multinational pivotal phase III study. Int J
Stroke 6, 362-367.
Angel I, Bar A, Horovitz T, Taler G, Krakovsky M, Resnitsky D, Rosenberg G, Striem S, Friedman JE, Kozak A
(2002) Metal ion chelation in neurodegenerative disorders.
Drug Dev Res 56, 300-309.
Yeung PK (2004) DP-b99 (D-Pharm). Curr Opin Investig
Drugs 5, 90-94.
Barkalifa R, Hershfinkel M, Friedman JE, Kozak A, Sekler
I (2009) The lipophilic zinc chelator DP-b99 prevents zinc
induced neuronal death. Eur J Pharmacol 618, 15-21.
Duce JA, Tsatsanis A, Cater MA, James SA, Robb E,
Wikhe K, Leong SL, Perez K, Johanssen T, Greenough
MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean
C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD,
Rogers JT, Bush AI (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc
in Alzheimer’s disease. Cell 142, 857-867.
Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames
D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW (2008) Safety, efficacy,
and biomarker findings of PBT2 in targeting Abeta as a
modifying therapy for Alzheimer’s disease: A phase IIa,
double-blind, randomised, placebo-controlled trial. Lancet
Neurol 7, 779-786.
Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis
A, Bedo J, Harrison J, Lannfelt L, Blennow K, Zetterberg
H, Ingelsson M, Masters CL, Tanzi RE, Cummings JL,
[495]
[496]
[497]
[498]
[499]
[500]
[501]
[502]
[503]
[504]
[505]
[506]
[507]
71
Herd CM, Bush AI (2010) PBT2 rapidly improves cognition in Alzheimer’s Disease: Additional phase II analyses.
J Alzheimers Dis 20, 509-516.
Adlard PA, James SA, Bush AI, Masters CL (2009) betaAmyloid as a molecular therapeutic target in Alzheimer’s
disease. Drugs Today (Barc) 45, 293-304.
Adlard PA, Bica L, White AR, Nurjono M, Filiz G, Crouch
PJ, Donnelly PS, Cappai R, Finkelstein DI, Bush AI (2011)
Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of
Alzheimer’s disease. PLoS One 6, e17669.
Crouch PJ, Savva MS, Hung LW, Donnelly PS, Mot AI,
Parker SJ, Greenough MA, Volitakis I, Adlard PA, Cherny
RA, Masters CL, Bush AI, Barnham KJ, White AR (2011)
The Alzheimer’s therapeutic PBT2 promotes amyloid-beta
degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem 119, 220-230.
Lee JY, Friedman JE, Angel I, Kozak A, Koh JY (2004) The
lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human beta-amyloid precursor protein
transgenic mice. Neurobiol Aging 25, 1315-1321.
Petri S, Calingasan NY, Alsaied OA, Wille E, Kiaei M,
Friedman JE, Baranova O, Chavez JC, Beal MF (2007) The
lipophilic metal chelators DP-109 and DP-460 are neuroprotective in a transgenic mouse model of amyotrophic
lateral sclerosis. J Neurochem 102, 991-1000.
Fine JM, Baillargeon AM, Renner DB, Hoerster NS,
Tokarev J, Colton S, Pelleg A, Andrews A, Sparley KA,
Krogh KM, Frey WH, Hanson LR (2012) Intranasal deferoxamine improves performance in radial arm water maze,
stabilizes HIF-1alpha, and phosphorylates GSK3beta in
P301L tau transgenic mice. Exp Brain Res 219, 381-390.
Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik
ZI, Warshawsky A, Youdim MB, Fridkin M (2005)
Design, synthesis, and evaluation of novel bifunctional
iron-chelators as potential agents for neuroprotection in
Alzheimer’s, Parkinson’s, and other neurodegenerative
diseases. Bioorg Med Chem 13, 773-783.
Zheng H, Youdim MB, Fridkin M (2009) Site-activated
multifunctional chelator with acetylcholinesterase and
neuroprotective-neurorestorative moieties for Alzheimer’s
therapy. J Med Chem 52, 4095-4098.
Jones MR, Service EL, Thompson JR, Wang MC, Kimsey
IJ, Detoma AS, Ramamoorthy A, Lim MH, Storr T (2012)
Dual-function triazole-pyridine derivatives as inhibitors of
metal-induced amyloid-beta aggregation. Metallomics 4,
910-920.
Youdim MB, Fridkin M, Zheng H (2005) Bifunctional drug
derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of
brain ageing and ageing neurodegenerative diseases. Mech
Ageing Dev 126, 317-326.
Youdim MB (2006) The path from anti Parkinson drug
selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30. Curr
Alzheimer Res 3, 541-550.
Gal S, Fridkin M, Amit T, Zheng H, Youdim MB (2006)
M30, a novel multifunctional neuroprotective drug with
potent iron chelating and brain selective monoamine
oxidase-ab inhibitory activity for Parkinson’s disease.
J Neural Transm Suppl 70, 447-456.
Avramovich-Tirosh Y, Amit T, Bar-Am O, Zheng H,
Fridkin M, Youdim MB (2007) Therapeutic targets and
potential of the novel brain- permeable multifunctional
iron chelator-monoamine oxidase inhibitor drug, M-30,
72
[508]
[509]
[510]
[511]
[512]
[513]
[514]
[515]
[516]
[517]
[518]
[519]
[520]
[521]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
for the treatment of Alzheimer’s disease. J Neurochem 100,
490-502.
Avramovich-Tirosh Y, Reznichenko L, Mit T, Zheng H,
Fridkin M, Weinreb O, Mandel S, Youdim MB (2007) Neurorescue activity, APP regulation and amyloid-beta peptide
reduction by novel multi-functional brain permeable ironchelating- antioxidants, M-30 and green tea polyphenol,
EGCG. Curr Alzheimer Res 4, 403-411.
Weinreb O, Mandel S, Bar-Am O, Yogev-Falach M,
Avramovich-Tirosh Y, Amit T, Youdim MB (2009) Multifunctional neuroprotective derivatives of rasagiline as
anti-Alzheimer’s disease drugs. Neurotherapeutics 6, 163174.
Weinreb O, Mandel S, Bar-Am O, Amit T (2011)
Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic
agents for Alzheimer’s disease: A tribute to Moussa
Youdim. J Neural Transm 118, 479-492.
Bar-Am O, Amit T, Weinreb O, Youdim MB, Mandel S
(2010) Propargylamine containing compounds as modulators of proteolytic cleavage of amyloid-beta protein
precursor: Involvement of MAPK and PKC activation.
J Alzheimers Dis 21, 361-371.
Johnson S, Tazik S, Lu D, Johnson C, Youdim MB, Wang
J, Rajkowska G, Ou XM (2010) The new inhibitor of
monoamine oxidase, M30, has a neuroprotective effect
against dexamethasone-induced brain cell apoptosis. Front
Neurosci 4, 180.
Zheng H, Fridkin M, Youdim MB (2010) Site-activated
chelators derived from anti-Parkinson drug rasagiline as a
potential safer and more effective approach to the treatment
of Alzheimer’s disease. Neurochem Res 35, 2117-2123.
Kupershmidt L, Amit T, Bar-Am O, Weinreb O,
Youdim MB (2012) Multi-target, neuroprotective and neurorestorative M30 improves cognitive impairment and
reduces Alzheimer’s-like neuropathology and age-related
alterations in mice. Mol Neurobiol 46, 217-220.
Kupershmidt L, Weinreb O, Amit T, Mandel S, Bar-Am
O, Youdim MB (2011) Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug
M30 in the mouse brain. Neuroscience 189, 345-358.
Kupershmidt L, Amit T, Bar-Am O, Youdim MB, Weinreb
O (2012) Neuroprotection by the multitarget iron chelator
M30 on age-related alterations in mice. Mech Ageing Dev
133, 267-274.
Kupershmidt L, Amit T, Bar-Am O, Youdim MB, Weinreb O (2012) The novel multi-target iron chelating-radical
scavenging compound M30 possesses beneficial effects on
major hallmarks of Alzheimer’s disease. Antioxid Redox
Signal 17, 860-877.
Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY,
Smith WL, Kalow W, Andrews DF (1991) Intramuscular desferrioxamine in patients with Alzheimer’s disease.
Lancet 337, 1304-1308.
Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush
AI (2000) Metal chelation as a potential therapy for
Alzheimer’s disease. Ann N Y Acad Sci 920, 292-304.
de Lima MN, Presti-Torres J, Caldana F, Grazziotin MM,
Scalco FS, Guimaraes MR, Bromberg E, Franke SI, Henriques JA, Schroder N (2007) Desferoxamine reverses
neonatal iron-induced recognition memory impairment in
rats. Eur J Pharmacol 570, 111-114.
Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones
WD, McLean CA, Barnham KJ, Volitakis I, Fraser
FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim
[522]
[523]
[524]
[525]
[526]
[527]
[528]
[529]
[530]
[531]
[532]
[533]
[534]
[535]
[536]
JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL,
Bush AI (2001) Treatment with a copper-zinc chelator
markedly and rapidly inhibits beta-amyloid accumulation
in Alzheimer’s disease transgenic mice. Neuron 30, 665676.
Ibach B, Haen E, Marienhagen J, Hajak G (2005) Clioquinol treatment in familiar early onset of Alzheimer’s
disease: A case report. Pharmacopsychiatry 38, 178-179.
Shachar DB, Kahana N, Kampel V, Warshawsky A,
Youdim MB (2004) Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine
lession in rats. Neuropharmacology 46, 254-263.
Youdim MB, Stephenson G, Ben SD (2004) Ironing
iron out in Parkinson’s disease and other neurodegenerative diseases with iron chelators: A lesson from
6-hydroxydopamine and iron chelators, desferal and VK28. Ann N Y Acad Sci 1012, 306-325.
Bandyopadhyay S, Huang X, Cho H, Greig NH,
Youdim MB, Rogers JT (2006) Metal specificity of
an iron-responsive element in Alzheimer’s APP mRNA
5’untranslated region, tolerance of SH-SY5Y and H4
neural cells to desferrioxamine, clioquinol, VK-28, and
a piperazine chelator. J Neural Transm Suppl 71, 237247.
Weinreb O, Mandel S, Bar-Am O, Yogev-Falach M,
Vramovich-Tirosh Y, Amit T, Youdim MB (2009) Multifunctional neuroprotective derivatives of rasagiline as
anti-Alzheimer’s disease drugs. Neurotherapeutics 6, 163174.
Akhondzadeh S, Abbasi SH (2006) Herbal medicine in
the treatment of Alzheimer’s disease. Am J Alzheimers Dis
Other Demen 21, 113-118.
Man SC, Durairajan SS, Kum WF, Lu JH, Huang JD,
Cheng CF, Chung V, Xu M, Li M (2008) Systematic
review on the efficacy and safety of herbal medicines for
Alzheimer’s disease. J Alzheimers Dis 14, 209-223.
Kim J, Lee HJ, Lee KW (2010) Naturally occurring phytochemicals for the prevention of Alzheimer’s disease.
J Neurochem 112, 1415-1430.
Kennedy DO, Wightman EL (2011) Herbal extracts
and phytochemicals: Plant secondary metabolites and
the enhancement of human brain function. Adv Nutr
(Bethesda) 2, 32-50.
Perry E, Howes MJ (2011) Medicinal plants and dementia
therapy: Herbal hopes for brain aging? CNS Neurosci Ther
17, 683-698.
Kim HG, Oh MS (2012) Herbal medicines for the prevention and treatment of Alzheimer’s disease. Curr Pharm
Des 18, 57-75.
Mancuso C, Siciliano R, Barone E, Preziosi P (2012) Natural substances and Alzheimer’s disease: From preclinical
studies to evidence based medicine. Biochim Biophys Acta
1822, 616-624.
Yoshitake T, Yoshitake S, Kehr J (2010) The Ginkgo biloba
extract EGb 761(R) and its main constituent flavonoids and
ginkgolides increase extracellular dopamine levels in the
rat prefrontal cortex. Br J Pharmacol 159, 659-668.
Han CK, Park YH, Jin DQ, Hwang YK, Oh KB, Han JS
(2007) SK-PC-B70M from Pulsatilla koreana improves
scopolamine-induced impairments of memory consolidation and spatial working memory. Brain Res 1184,
254-259.
Han CK, Choi WR, Oh KB (2007) Cognition-enhancing
and neuroprotective effects of hederacolchiside-E from
Pulsatilla koreana. Planta Med 73, 665-669.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[537]
[538]
[539]
[540]
[541]
[542]
[543]
[544]
[545]
[546]
[547]
[548]
[549]
[550]
[551]
Seo JS, Kim TK, Leem YH, Lee KW, Park SK, Baek IS,
Kim KS, Im GJ, Lee SM, Park YH, Han PL (2009) SKPC-B70M confers anti-oxidant activity and reduces Abeta
levels in the brain of Tg2576 mice. Brain Res 1261, 100108.
Seo JS, Baek IS, Leem YH, Kim TK, Cho Y, Lee SM, Park
YH, Han PL (2011) SK-PC-B70M alleviates neurologic
symptoms in G93A-SOD1 amyotrophic lateral sclerosis
mice. Brain Res 1368, 299-307.
Baur JA, Sinclair DA (2006) Therapeutic potential of
resveratrol: The in vivo evidence. Nat Rev Drug Discov
5, 493-506.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C,
Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K,
Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang
M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta
EG, Le CD, Shaw RJ, Navas P, Puigserver P, Ingram DK,
de CR, Sinclair DA (2006) Resveratrol improves health
and survival of mice on a high-calorie diet. Nature 444,
337-342.
Baur JA (2010) Resveratrol, sirtuins, and the promise of a
DR mimetic. Mech Ageing Dev 131, 261-269.
Baur JA, Chen D, Chini EN, Chua K, Cohen HY, de
CR, Deng C, Dimmeler S, Gius D, Guarente LP, Helfand
SL, Imai S, Itoh H, Kadowaki T, Koya D, Leeuwenburgh
C, McBurney M, Nabeshima Y, Neri C, Oberdoerffer P,
Pestell RG, Rogina B, Sadoshima J, Sartorelli V, Serrano
M, Sinclair DA, Steegborn C, Tatar M, Tissenbaum HA,
Tong Q, Tsubota K, Vaquero A, Verdin E (2010) Dietary
restriction: Standing up for sirtuins. Science 329, 10121013.
Kennedy DO, Wightman EL, Reay JL, Lietz G, Okello
EJ, Wilde A, Haskell CF (2010) Effects of resveratrol on
cerebral blood flow variables and cognitive performance
in humans: A double-blind, placebo-controlled, crossover
investigation. Am J Clin Nutr 91, 1590-1597.
Quideau S, Deffieux D, Pouysegu L (2012) Resveratrol
still has something to say about aging! Angew Chem Int
Ed Engl 51, 6824-6826.
Marambaud P, Zhao H, Davies P (2005) Resveratrol
promotes clearance of Alzheimer’s disease amyloid-beta
peptides. J Biol Chem 280, 37377-37382.
Albani D, Polito L, Batelli S, De MS, Fracasso C, Martelli
G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro
A, Forloni G (2009) The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against
toxicity caused by alpha-synuclein or amyloid-beta (1-42)
peptide. J Neurochem 110, 1445-1456.
Albani D, Polito L, Forloni G (2010) Sirtuins as novel
targets for Alzheimer’s disease and other neurodegenerative disorders: Experimental and genetic evidence.
J Alzheimers Dis 19, 11-26.
Albani D, Polito L, Signorini A, Forloni G (2010)
Neuroprotective properties of resveratrol in different neurodegenerative disorders. Biofactors 36, 370-376.
Ladiwala AR, Lin JC, Bale SS, Marcelino-Cruz AM, Bhattacharya M, Dordick JS, Tessier PM (2010) Resveratrol
selectively remodels soluble oligomers and fibrils of amyloid Abeta into off-pathway conformers. J Biol Chem 285,
24228-24237.
Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L,
Wang M (2009) Resveratrol is not a direct activator of
SIRT1 enzyme activity. Chem Biol Drug Des 74, 619-624.
Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ,
Kang SS, Cho GJ, Choi WS, Roh GS (2012) Resvera-
[552]
[553]
[554]
[555]
[556]
[557]
[558]
[559]
[560]
[561]
[562]
[563]
[564]
[565]
[566]
73
trol attenuates obesity-associated peripheral and central
inflammation and improves memory deficit in mice fed a
high-fat diet. Diabetes 61, 1444-1454.
Johnson WD, Morrissey RL, Usborne AL, Kapetanovic
I, Crowell JA, Muzzio M, McCormick DL (2011)
Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring
polyphenol with cancer preventive activity. Food Chem
Toxicol 49, 3319-3327.
Zhang Y, Li SZ, Li J, Pan X, Cahoon RE, Jaworski JG,
Wang X, Jez JM, Chen F, Yu O (2006) Using unnatural
protein fusions to engineer resveratrol biosynthesis in yeast
and Mammalian cells. J Am Chem Soc 128, 13030-13031.
Pasinetti GM, Wang J, Marambaud P, Ferruzzi M, Gregor
P, Knable LA, Ho L (2011) Neuroprotective and metabolic
effects of resveratrol: Therapeutic implications for Huntington’s disease and other neurodegenerative disorders.
Exp Neurol 232, 1-6.
Wang Y, Xia Z, Xu JR, Wang YX, Hou LN, Qiu
Y, Chen HZ (2012) Alpha-mangostin, a polyphenolic
xanthone derivative from mangosteen, attenuates betaamyloid oligomers-induced neurotoxicity by inhibiting
amyloid aggregation. Neuropharmacology 62, 871-881.
Paris D, Beaulieu-Abdelahad D, Bachmeier C, Reed J, itGhezala G, Bishop A, Chao J, Mathura V, Crawford F,
Mullan M (2011) Anatabine lowers Alzheimer’s Abeta
production in vitro and in vivo. Eur J Pharmacol 670,
384-391.
Radhika P, Annapurna A, Rao SN (2012) Immunostimulant, cerebroprotective & nootropic activities of
Andrographis paniculata leaves extract in normal & type
2 diabetic rats. Indian J Med Res 135, 636-641.
Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A,
Teichberg S, Callaway DJ (2002) New class of inhibitors of
amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer’s disease. J Biol Chem
277, 42881-42890.
Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi
K, Sakae N, Motomura K, Soejima N, Yamasaki R,
Hashimoto T, Tabira T, LaFerla FM, Kira J (2011)
Apomorphine treatment in Alzheimer mice promoting
amyloid-beta degradation. Ann Neurol 69, 248-256.
Steele JW, Gandy S (2011) Apomorphine and Alzheimer
Abeta: Roles for regulated alpha cleavage, autophagy, and
antioxidation? Ann Neurol 69, 221-225.
Howland RH (2010) Drug therapies for cognitive impairment and dementia. J Psychosoc Nurs Ment Health Serv
48, 11-14.
Roman MW (2010) Axona (Accera, Inc): A new medical
food therapy for persons with Alzheimer’s disease. Issues
Ment Health Nurs 31, 435-436.
Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD,
Watson GS, Hyde K, Chapman D, Craft S (2004) Effects
of beta-hydroxybutyrate on cognition in memory-impaired
adults. Neurobiol Aging 25, 311-314.
Costantini LC, Barr LJ, Vogel JL, Henderson ST (2008)
Hypometabolism as a therapeutic target in Alzheimer’s
disease. BMC Neurosci 9(Suppl 2), S16.
Pocernich CB, Lange ML, Sultana R, Butterfield DA
(2011) Nutritional approaches to modulate oxidative stress
in Alzheimer’s disease. Curr Alzheimer Res 8, 452469.
Pase MP, Kean J, Sarris J, Neale C, Scholey AB, Stough
C (2012) The cognitive-enhancing effects of Bacopa
monnieri: A systematic review of randomized, controlled
74
[567]
[568]
[569]
[570]
[571]
[572]
[573]
[574]
[575]
[576]
[577]
[578]
[579]
[580]
[581]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
human clinical trials. J Altern Complement Med 18, 647652.
Saini N, Singh D, Sandhir R (2012) Neuroprotective
effects of Bacopa monnieri in experimental model of
dementia. Neurochem Res 37, 1928-1937.
Lebeau A, Esclaire F, Rostene W, Pelaprat D (2001)
Baicalein protects cortical neurons from beta-amyloid (2535) induced toxicity. Neuroreport 12, 2199-2202.
Wang SY, Wang HH, Chi CW, Chen CF, Liao JF (2004)
Effects of baicalein on beta-amyloid peptide-(25-35)induced amnesia in mice. Eur J Pharmacol 506, 55-61.
Yin F, Liu J, Ji X, Wang Y, Zidichouski J, Zhang J (2011)
Baicalin prevents the production of hydrogen peroxide
and oxidative stress induced by Abeta aggregation in SHSY5Y cells. Neurosci Lett 492, 76-79.
Gauci AJ, Caruana M, Giese A, Scerri C, Vassallo N (2011)
Identification of polyphenolic compounds and black tea
extract as potent inhibitors of lipid membrane destabilization by abeta42 aggregates. J Alzheimers Dis 27,
767-779.
Lu JH, Ardah MT, Durairajan SS, Liu LF, Xie LX, Fong
WF, Hasan MY, Huang JD, El-Agnaf OM, Li M (2011)
Baicalein inhibits formation of alpha-synuclein oligomers
within living cells and prevents Abeta peptide fibrillation
and oligomerisation. Chembiochem 12, 615-624.
Geng Y, Li C, Liu J, Xing G, Zhou L, Dong M, Li X,
Niu Y (2010) Beta-asarone improves cognitive function
by suppressing neuronal apoptosis in the beta-amyloid
hippocampus injection rats. Biol Pharm Bull 33, 836-843.
Li C, Xing G, Dong M, Zhou L, Li J, Wang G, Zou D, Wang
R, Liu J, Niu Y (2010) Beta-asarone protection against
beta-amyloid-induced neurotoxicity in PC12 cells via JNK
signaling and modulation of Bcl-2 family proteins. Eur J
Pharmacol 635, 96-102.
Liu J, Li C, Xing G, Zhou L, Dong M, Geng Y, Li X,
Li J, Wang G, Zou D, Niu Y (2010) Beta-asarone attenuates neuronal apoptosis induced by Beta amyloid in rat
hippocampus. Yakugaku Zasshi 130, 737-746.
Lee JY, Kim KY, Shin KY, Won BY, Jung HY, Suh YH
(2009) Effects of BT-11 on memory in healthy humans.
Neurosci Lett 454, 111-114.
Shin KY, Won BY, Heo C, Kim HJ, Jang DP, Park CH,
Kim S, Kim HS, Kim YB, Lee HG, Lee SH, Cho ZH,
Suh YH (2009) BT-11 improves stress-induced memory
impairments through increment of glucose utilization and
total neural cell adhesion molecule levels in rat brains.
J Neurosci Res 87, 260-268.
Shin KY, Lee JY, Won BY, Jung HY, Chang KA, Koppula
S, Suh YH (2009) BT-11 is effective for enhancing cognitive functions in the elderly humans. Neurosci Lett 465,
157-159.
Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein
DL, Thiyagarajan M, Percival SS, Talcott ST, Pasinetti
GM (2006) Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model
of Alzheimer’s disease. FASEB J 20, 2313-2320.
Azizi Z, Ebrahimi S, Saadatfar E, Kamalinejad M, Majlessi N (2012) Cognitive-enhancing activity of thymol and
carvacrol in two rat models of dementia. Behav Pharmacol
23, 241-249.
Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H,
Yamada M (2003) Potent anti-amyloidogenic and fibrildestabilizing effects of polyphenols in vitro: Implications
for the prevention and therapeutics of Alzheimer’s disease.
J Neurochem 87, 172-181.
[582]
[583]
[584]
[585]
[586]
[587]
[588]
[589]
[590]
[591]
[592]
[593]
[594]
[595]
[596]
Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim
MB (2008) Targeting multiple neurodegenerative diseases
etiologies with multimodal-acting green tea catechins.
J Nutr 138, 1578S-1583S.
Ferruzzi MG, Lobo JK, Janle EM, Cooper B, Simon JE,
Wu QL, Welch C, Ho L, Weaver C, Pasinetti GM (2009)
Bioavailability of gallic acid and catechins from grape
seed polyphenol extract is improved by repeated dosing
in rats: Implications for treatment in Alzheimer’s disease.
J Alzheimers Dis 18, 113-124.
Paris D, Ganey NJ, Laporte V, Patel NS, BeaulieuAbdelahad D, Bachmeier C, March A, it-Ghezala G,
Mullan MJ (2010) Reduction of beta-amyloid pathology
by celastrol in a transgenic mouse model of Alzheimer’s
disease. J Neuroinflammation 7, 17.
Bhanumathy M, Harish MS, Shivaprasad HN, Sushma G
(2010) Nootropic activity of Celastrus paniculatus seed.
Pharm Biol 48, 324-327.
Frydman-Marom A, Levin A, Farfara D, Benromano T,
Scherzer-Attali R, Peled S, Vassar R, Segal D, Gazit E,
Frenkel D, Ovadia M (2011) Orally administrated cinnamon extract reduces beta-amyloid oligomerization and
corrects cognitive impairment in Alzheimer’s disease animal models. PLoS One 6, e16564.
Marumoto S, Miyazawa M (2012) Structure-activity
relationships for naturally occurring coumarins as betasecretase inhibitor. Bioorg Med Chem 20, 784-788.
Anand P, Singh B, Singh N (2012) A review on coumarins
as acetylcholinesterase inhibitors for Alzheimer’s disease.
Bioorg Med Chem 20, 1175-1180.
Mei Z, Yan P, Situ B, Mou Y, Liu P (2012) Cryptotanshinione inhibits beta-amyloid aggregation and protects
damage from beta-amyloid in SH-SY5Y cells. Neurochem
Res 37, 622-628.
Mei Z, Situ B, Tan X, Zheng S, Zhang F, Yan P, Liu P
(2010) Cryptotanshinione upregulates alpha-secretase by
activation PI3K pathway in cortical neurons. Brain Res
1348, 165-173.
Jiang T, Zhi XL, Zhang YH, Pan LF, Zhou P (2012)
Inhibitory effect of curcumin on the Al(III)-induced
Abeta(42) aggregation and neurotoxicity in vitro. Biochim
Biophys Acta 1822, 1207-1215.
Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole
GM (2001) The curry spice curcumin reduces oxidative
damage and amyloid pathology in an Alzheimer transgenic
mouse. J Neurosci 21, 8370-8377.
Ono K, Hasegawa K, Naiki H, Yamada M (2004)
Curcumin has potent anti-amyloidogenic effects for
Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res
75, 742-750.
Ringman JM, Frautschy SA, Cole GM, Masterman DL,
Cummings JL (2005) A potential role of the curry spice
curcumin in Alzheimer’s disease. Curr Alzheimer Res 2,
131-136.
Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons
MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG,
Frautschy SA, Cole GM (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques,
and reduces amyloid in vivo. J Biol Chem 280, 58925901.
Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT,
Bacskai BJ (2007) Curcumin labels amyloid pathology in
vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem
102, 1095-1104.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[597]
[598]
[599]
[600]
[601]
[602]
[603]
[604]
[605]
[606]
[607]
[608]
[609]
[610]
[611]
Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath
DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S,
Faull KF, Teter B, Cole GM, Frautschy SA (2008) Curcumin structure-function, bioavailability, and efficacy in
models of neuroinflammation and Alzheimer’s disease.
J Pharmacol Exp Ther 326, 196-208.
Park SY, Kim HS, Cho EK, Kwon BY, Phark S, Hwang
KW, Sul D (2008) Curcumin protected PC12 cells against
beta-amyloid-induced toxicity through the inhibition of
oxidative damage and tau hyperphosphorylation. Food
Chem Toxicol 46, 2881-2887.
Hamaguchi T, Ono K, Murase A, Yamada M (2009) Phenolic compounds prevent Alzheimer’s pathology through
different effects on the amyloid-beta aggregation pathway.
Am J Pathol 175, 2557-2565.
Hamaguchi T, Ono K, Yamada M (2010) REVIEW: Curcumin and Alzheimer’s disease. CNS Neurosci Ther 16,
285-297.
Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant
DJ, Chen PP, Hudspeth B, Chen C, Zhao Y, Vinters HV,
Frautschy SA, Cole GM (2009) Beta-amyloid oligomers
induce phosphorylation of tau and inactivation of insulin
receptor substrate via c-Jun N-terminal kinase signaling:
Suppression by omega-3 fatty acids and curcumin. J Neurosci 29, 9078-9089.
Ray B, Lahiri DK (2009) Neuroinflammation in
Alzheimer’s disease: Different molecular targets and
potential therapeutic agents including curcumin. Curr
Opin Pharmacol 9, 434-444.
Zhang C, Browne A, Child D, Tanzi RE (2010) Curcumin
decreases amyloid-beta peptide levels by attenuating the
maturation of amyloid-beta precursor protein. J Biol Chem
285, 28472-28480.
Ferrari E, Pignedoli F, Imbriano C, Marverti G, Basile V,
Venturi E, Saladini M (2011) Newly synthesized curcumin
derivatives: Crosstalk between chemico-physical properties and biological activity. J Med Chem 54, 8066-8077.
Gupta SC, Prasad S, Kim JH, Patchva S, Webb LJ,
Priyadarsini IK, Aggarwal BB (2011) Multitargeting by
curcumin as revealed by molecular interaction studies. Nat
Prod Rep 28, 1937-1955.
Mancuso C, Siciliano R, Barone E (2011) Curcumin and
Alzheimer disease: This marriage is not to be performed.
J Biol Chem 286, le3.
Ray B, Bisht S, Maitra A, Maitra A, Lahiri DK (2011) Neuroprotective and neurorescue effects of a novel polymeric
nanoparticle formulation of curcumin (NanoCurc) in the
neuronal cell culture and animal model: Implications for
Alzheimer’s disease. J Alzheimers Dis 23, 61-77.
Mourtas S, Canovi M, Zona C, Aurilia D, Niarakis A,
La FB, Salmona M, Nicotra F, Gobbi M, Antimisiaris
SG (2011) Curcumin-decorated nanoliposomes with very
high affinity for amyloid-beta1-42 peptide. Biomaterials
32, 1635-1645.
Reinke AA, Gestwicki JE (2007) Structure-activity relationships of amyloid beta-aggregation inhibitors based on
curcumin: Influence of linker length and flexibility. Chem
Biol Drug Des 70, 206-215.
Narlawar R, Pickhardt M, Leuchtenberger S, Baumann K,
Krause S, Dyrks T, Weggen S, Mandelkow E, Schmidt
B (2008) Curcumin-derived pyrazoles and isoxazoles:
Swiss army knives or blunt tools for Alzheimer’s disease?
ChemMedChem 3, 165-172.
Orlando RA, Gonzales AM, Royer RE, Deck LM, Vander Jagt DL (2012) A chemical analog of curcumin as
[612]
[613]
[614]
[615]
[616]
[617]
[618]
[619]
[620]
[621]
[622]
[623]
[624]
75
an improved inhibitor of amyloid Abeta oligomerization.
PLoS One 7, e31869.
Zhang Y, Saito H, Nishiyama N, Abe K (1994) Effects
of DX-9386, a traditional Chinese medicinal prescription,
on long-term potentiation in the dentate gyrus in rats. Biol
Pharm Bull 17, 1337-1340
Yang SG, Zhang X, Sun XS, Ling TJ, Feng Y, Du XY,
Zhao M, Yang Y, Xue D, Wang L, Liu RT (2010) Diverse
ecdysterones show different effects on amyloid-beta42
aggregation but all uniformly inhibit amyloid-beta42induced cytotoxicity. J Alzheimers Dis 22, 107-117.
Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J,
Town T, Tan J (2005) Green tea epigallocatechin-3-gallate
(EGCG) modulates amyloid precursor protein cleavage
and reduces cerebral amyloidosis in Alzheimer transgenic
mice. J Neurosci 25, 8807-8814.
Rezai-Zadeh K, Arendash GW, Hou H, Fernandez F,
Jensen M, Runfeldt M, Shytle RD, Tan J (2008) Green tea
epigallocatechin-3-gallate (EGCG) reduces beta-amyloid
mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res 1214,
177-187.
Rezai-Zadeh K, Douglas SR, Bai Y, Tian J, Hou H,
Mori T, Zeng J, Obregon D, Town T, Tan J (2009)
Flavonoid-mediated presenilin-1 phosphorylation reduces
Alzheimer’s disease beta-amyloid production. J Cell Mol
Med 13, 574-588.
Lee JW, Lee YK, Ban JO, Ha TY, Yun YP, Han SB,
Oh KW, Hong JT (2009) Green tea (–)-epigallocatechin3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via
inhibition of ERK and NF-kappaB pathways in mice.
J Nutr 139, 1987-1993.
Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H,
Neugebauer K, Wanker EE (2010) EGCG remodels mature
alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proc Natl Acad Sci U S A 107, 7710-7715.
Mandel SA, Avramovich-Tirosh Y, Reznichenko L, Zheng
H, Weinreb O, Amit T, Youdim MB (2005) Multifunctional activities of green tea catechins in neuroprotection.
Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals 14,
46-60.
Mandel SA, Amit T, Weinreb O, Reznichenko L, Youdim
MB (2008) Simultaneous manipulation of multiple brain
targets by green tea catechins: A potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS
Neurosci Ther 14, 352-365.
Mandel SA, Amit T, Kalfon L, Reznichenko L, Weinreb O, Youdim MB (2008) Cell signaling pathways and
iron chelation in the neurorestorative activity of green tea
polyphenols: Special reference to epigallocatechin gallate
(EGCG). J Alzheimers Dis 15, 211-222.
Mandel SA, Amit T, Weinreb O, Youdim MB (2011)
Understanding the broad-spectrum neuroprotective action
profile of green tea polyphenols in aging and neurodegenerative diseases. J Alzheimers Dis 25, 187-208.
Mandel SA, Weinreb O, Amit T, Youdim MB (2012)
The importance of the multiple target action of green tea
polyphenols for neuroprotection. Front Biosci (Schol Ed)
4, 581-598.
Kalfon L, Youdim MB, Mandel SA (2007) Green
tea polyphenol (–) -epigallocatechin-3-gallate promotes
the rapid protein kinase C- and proteasome-mediated
76
[625]
[626]
[627]
[628]
[629]
[630]
[631]
[632]
[633]
[634]
[635]
[636]
[637]
[638]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
degradation of Bad: Implications for neuroprotection.
J Neurochem 100, 992-1002.
Lopez Del Amo JM, Fink U, Dasari M, Grelle G, Wanker
EE, Bieschke J, Reif B (2012) Structural properties
of EGCG-induced, nontoxic Alzheimer’s disease Abeta
oligomers. J Mol Biol 421, 517-524.
Fernandez JW, Rezai-Zadeh K, Obregon D, Tan J
(2010) EGCG functions through estrogen receptormediated activation of ADAM10 in the promotion of
non-amyloidogenic processing of APP. FEBS Lett 584,
4259-4267.
Obregon DF, Rezai-Zadeh K, Bai Y, Sun N, Hou H, Ehrhart
J, Zeng J, Mori T, Arendash GW, Shytle D, Town T,
Tan J (2006) ADAM10 activation is required for green
tea (–)-epigallocatechin-3-gallate-induced alpha-secretase
cleavage of amyloid precursor protein. J Biol Chem 281,
16419-16427.
Smith A, Giunta B, Bickford PC, Fountain M, Tan
J, Shytle RD (2010) Nanolipidic particles improve the
bioavailability and alpha-secretase inducing ability of
epigallocatechin-3-gallate (EGCG) for the treatment of
Alzheimer’s disease. Int J Pharm 389, 207-212.
Kang SY, Lee KY, Koo KA, Yoon JS, Lim SW, Kim YC,
Sung SH (2005) ESP-102, a standardized combined extract
of Angelica gigas, Saururus chinensis and Schizandra
chinensis, significantly improved scopolamine-induced
memory impairment in mice. Life Sci 76, 1691-1705.
Kim DH, Jung WY, Park SJ, Kim JM, Lee S, Kim
YC, Ryu JH (2010) Anti-amnesic effect of ESP-102 on
Abeta(1-42)-induced memory impairment in mice. Pharmacol Biochem Behav 97, 239-248.
Kwon SH, Lee HK, Kim JA, Hong SI, Kim SY, Jo TH,
Park YI, Lee CK, Kim YB, Lee SY, Jang CG (2011)
Neuroprotective effects of Eucommia ulmoides Oliv. Bark
on amyloid beta(25-35)-induced learning and memory
impairments in mice. Neurosci Lett 487, 123-127.
Williams RJ, Spencer JP (2012) Flavonoids, cognition, and
dementia: Actions, mechanisms, and potential therapeutic
utility for Alzheimer disease. Free Radic Biol Med 52,
35-45.
Spencer JP, Vafeiadou K, Williams RJ, Vauzour D (2012)
Neuroinflammation: Modulation by flavonoids and mechanisms of action. Mol Aspects Med 33, 83-97.
Paris D, Mathura V, it-Ghezala G, Beaulieu-Abdelahad
D, Patel N, Bachmeier C, Mullan M (2011) Flavonoids
lower Alzheimer’s Abeta production via an NFkappaB
dependent mechanism. Bioinformation 6, 229-236.
Zhu JT, Choi RC, Chu GK, Cheung AW, Gao QT, Li
J, Jiang ZY, Dong TT, Tsim KW (2007) Flavonoids
possess neuroprotective effects on cultured pheochromocytoma PC12 cells: A comparison of different flavonoids
in activating estrogenic effect and in preventing betaamyloid-induced cell death. J Agric Food Chem 55,
2438-2445.
Uriarte-Pueyo I, Calvo MI (2011) Flavonoids as acetylcholinesterase inhibitors. Curr Med Chem 18, 5289-5302.
Thapa A, Woo ER, Chi EY, Sharoar MG, Jin HG,
Shin SY, Park IS (2011) Biflavonoids are superior to
monoflavonoids in inhibiting amyloid-beta toxicity and
fibrillogenesis via accumulation of nontoxic oligomer-like
structures. Biochemistry 50, 2445-2455.
Broersen LM, Kuipers AA, Balvers M, van WN, Savelkoul
PJ, de Wilde MC, van der Beek EM, Sijben JW, Hageman
RJ, Kamphuis PJ, Kiliaan AJ (2012) A specific multinutrient diet reduces Alzheimer-like pathology in young
[639]
[640]
[641]
[642]
[643]
[644]
[645]
[646]
[647]
[648]
[649]
[650]
[651]
[652]
[653]
[654]
adult AbetaPPswe/PS1dE9 mice. J Alzheimers Dis, doi:
10.3233/JAD-2012-112039 [Epub ahead of print].
Cornejo A, Jimenez JM, Caballero L, Melo F, Maccioni
RB (2011) Fulvic acid inhibits aggregation and promotes
disassembly of tau fibrils associated with Alzheimer’s disease. J Alzheimers Dis 27, 143-153.
Selassie M, Griffin B, Gwebu N, Gwebu ET (1999) Aged
garlic extract attenuates the cytotoxicity of beta-amyloid
on undifferentiated PC12 cells. In Vitro Cell Dev Biol Anim
35, 369-370.
Griffin B, Selassie M, Gwebu ET (2000) Aged garlic
extract suppresses lipid peroxidation induced by betaamyloid in PC12 cells. In Vitro Cell Dev Biol Anim 36,
279-280.
Peng Q, Buz’Zard AR, Lau BH (2002) Neuroprotective effect of garlic compounds in amyloid-beta
peptide-induced apoptosis in vitro. Med Sci Monit 8,
BR328-BR337.
Gupta VB, Indi SS, Rao KS (2009) Garlic extract exhibits
antiamyloidogenic activity on amyloid-beta fibrillogenesis: Relevance to Alzheimer’s disease. Phytother Res 23,
111-115.
Chauhan NB (2006) Effect of aged garlic extract on APP
processing and tau phosphorylation in Alzheimer’s transgenic model Tg2576. J Ethnopharmacol 108, 385-394.
Chauhan NB, Sandoval J (2007) Amelioration of early
cognitive deficits by aged garlic extract in Alzheimer’s
transgenic mice. Phytother Res 21, 629-640.
Ray B, Chauhan NB, Lahiri DK (2011) The “aged garlic
extract:” (AGE) and one of its active ingredients S-allylL-cysteine (SAC) as potential preventive and therapeutic
agents for Alzheimer’s disease (AD). Curr Med Chem 18,
3306-3313.
Stackman RW, Eckenstein F, Frei B, Kulhanek D, Nowlin
J, Quinn JF (2003) Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer’s
disease by chronic Ginkgo biloba treatment. Exp Neurol
184, 510-520.
Tchantchou F, Xu Y, Wu Y, Christen Y, Luo Y (2007)
EGb 761 enhances adult hippocampal neurogenesis and
phosphorylation of CREB in transgenic mouse model of
Alzheimer’s disease. FASEB J 21, 2400-2408.
Defeudis FV, Drieu K (2000) Ginkgo biloba extract (EGb
761) and CNS functions: Basic studies and clinical applications. Curr Drug Targets 1, 25-58.
Defeudis FV (2003) A brief history of EGb 761 and its
therapeutic uses. Pharmacopsychiatry 36(Suppl 1), S2-S7.
Allain H, Raoul P, Lieury A, LeCoz F, Gandon JM,
D’Arbigny P (1993) Effect of two doses of ginkgo biloba
extract (EGb 761) on the dual-coding test in elderly subjects. Clin Ther 15, 549-558.
Le Bars PL, Katz MM, Berman N, Itil TM, Freedman
AM, Schatzberg AF (1997) A placebo-controlled, doubleblind, randomized trial of an extract of Ginkgo biloba for
dementia. North American EGb Study Group. JAMA 278,
1327-1332.
Le Bars PL, Kieser M, Itil KZ (2000) A 26-week analysis
of a double-blind, placebo-controlled trial of the ginkgo
biloba extract EGb 761 in dementia. Dement Geriatr Cogn
Disord 11, 230-237.
Le Bars PL, Velasco FM, Ferguson JM, Dessain EC, Kieser
M, Hoerr R (2002) Influence of the severity of cognitive
impairment on the effect of the Gnkgo biloba extract EGb
761 in Alzheimer’s disease. Neuropsychobiology 45, 1926.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[655]
[656]
[657]
[658]
[659]
[660]
[661]
[662]
[663]
[664]
[665]
[666]
[667]
[668]
[669]
Le Bars PL (2003) Magnitude of effect and special
approach to Ginkgo biloba extract EGb 761 in cognitive
disorders. Pharmacopsychiatry 36(Suppl 1), S44-S49.
Le Bars PL (2003) Response patterns of EGb 761 in
Alzheimer’s disease: Influence of neuropsychological profiles. Pharmacopsychiatry 36(Suppl 1), S50-S55.
Oken BS, Storzbach DM, Kaye JA (1998) The efficacy of
Ginkgo biloba on cognitive function in Alzheimer disease.
Arch Neurol 55, 1409-1415.
Mix JA, Crews WD Jr (2000) An examination of the
efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults.
J Altern Complement Med 6, 219-229.
Mix JA, Crews WD Jr (2002) A double-blind, placebocontrolled, randomized trial of Ginkgo biloba extract
EGb 761 in a sample of cognitively intact older adults:
Neuropsychological findings. Hum Psychopharmacol 17,
267-277.
Dekosky ST, Fitzpatrick A, Ives DG, Saxton J, Williamson
J, Lopez OL, Burke G, Fried L, Kuller LH, Robbins
J, Tracy R, Woolard N, Dunn L, Kronmal R, Nahin R,
Furberg C (2006) The Ginkgo Evaluation of Memory
(GEM) study: Design and baseline data of a randomized
trial of Ginkgo biloba extract in prevention of dementia.
Contemp Clin Trials 27, 238-253.
Dekosky ST, Furberg CD (2008) Turning over a new leaf:
Ginkgo biloba in prevention of dementia? Neurology 70,
1730-1731.
Mazza M, Capuano A, Bria P, Mazza S (2006) Ginkgo
biloba and donepezil: A comparison in the treatment of
Alzheimer’s dementia in a randomized placebo-controlled
double-blind study. Eur J Neurol 13, 981-985.
Snitz BE, O’Meara ES, Carlson MC, Arnold AM, Ives
DG, Rapp SR, Saxton J, Lopez OL, Dunn LO, Sink KM,
Dekosky ST (2009) Ginkgo biloba for preventing cognitive
decline in older adults: A randomized trial. JAMA 302,
2663-2670.
Yancheva S, Ihl R, Nikolova G, Panayotov P, Schlaefke S, Hoerr R (2009) Ginkgo biloba extract EGb
761(R), donepezil or both combined in the treatment of
Alzheimer’s disease with neuropsychiatric features: A
randomised, double-blind, exploratory trial. Aging Ment
Health 13, 183-190.
Janssen IM, Sturtz S, Skipka G, Zentner A, Velasco GM,
Busse R (2010) Ginkgo biloba in Alzheimer’s disease:
A systematic review. Wien Med Wochenschr 160, 539546.
Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen
L, Humala N, Teplow DB, Pasinetti GM (2008) Grapederived polyphenolics prevent Abeta oligomerization and
attenuate cognitive deterioration in a mouse model of
Alzheimer’s disease. J Neurosci 28, 6388-6392.
Ksiezak-Reding H, Ho L, Santa-Maria I, az-Ruiz C,
Wang J, Pasinetti GM (2012) Ultrastructural alterations of
Alzheimer’s disease paired helical filaments by grape seedderived polyphenols. Neurobiol Aging 33, 1427-1439.
Tarozzi A, Merlicco A, Morroni F, Bolondi C, Di IP, Ciccarelli R, Romano S, Giuliani P, Hrelia P (2010) Guanosine
protects human neuroblastoma cells from oxidative stress
and toxicity induced by Amyloid-beta peptide oligomers.
J Biol Regul Homeost Agents 24, 297-306.
Bao Q, Luo Y, Li W, Sun X, Zhu C, Li P, Huang ZX, Tan X
(2011) The mechanism for heme to prevent Abeta(1-40)
aggregation and its cytotoxicity. J Biol Inorg Chem 16,
809-816.
[670]
[671]
[672]
[673]
[674]
[675]
[676]
[677]
[678]
[679]
[680]
[681]
[682]
[683]
[684]
77
Dong X, Geng M, Guan H (2003) Effects of the marine
acidic oligose on dopamine release from striatum and
amygdala in the rat model of Parkinson’s disease. Chin
J Marine Drugs 22, 9-12.
Zeng KW, Wang XM, Ko H, Kwon HC, Cha JW, Yang
HO (2011) Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid beta-protein
via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial
apoptotic pathway. Eur J Pharmacol 672, 45-55.
Nie J, Luo Y, Huang XN, Gong QH, Wu Q, Shi JS
(2010) Icariin inhibits beta-amyloid peptide segment
25-35 induced expression of beta-secretase in rat hippocampus. Eur J Pharmacol 626, 213-218.
Zeng KW, Ko H, Yang HO, Wang XM (2010) Icariin
attenuates beta-amyloid-induced neurotoxicity by inhibition of tau protein hyperphosphorylation in PC12 cells.
Neuropharmacology 59, 542-550.
Zeng KW, Fu H, Liu GX, Wang XM (2010) Icariin
attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting
TAK1/IKK/NF-kappaB and JNK/p38 MAPK pathways.
Int Immunopharmacol 10, 668-678.
Urano T, Tohda C (2010) Icariin improves memory impairment in Alzheimer’s disease model mice (5xFAD) and
attenuates amyloid beta-induced neurite atrophy. Phytother Res 24, 1658-1663.
Zheng M, Qu L, Lou Y (2008) Effects of icariin combined
with Panax notoginseng saponins on ischemia reperfusioninduced cognitive impairments related with oxidative
stress and CA1 of hippocampal neurons in rat. Phytother
Res 22, 597-604.
Carvajal FJ, Inestrosa NC (2011) Interactions of AChE
with Abeta aggregates in Alzheimer’s brain: Therapeutic
relevance of IDN 5706. Front Mol Neurosci 4, 19.
Roth A, Schaffner W, Hertel C (1999) Phytoestrogen
kaempferol (3,4 ,5,7-tetrahydroxyflavone) protects PC12
and T47D cells from beta-amyloid-induced toxicity. J Neurosci Res 57, 399-404.
Kim JK, Choi SJ, Cho HY, Hwang HJ, Kim YJ, Lim ST,
Kim CJ, Kim HK, Peterson S, Shin DH (2010) Protective effects of kaempferol (3,4 ,5,7-tetrahydroxyflavone)
against amyloid beta peptide (Abeta)-induced neurotoxicity in ICR mice. Biosci Biotechnol Biochem 74, 397-401.
Lee KY, Sung SH, Kim SH, Jang YP, Oh TH, Kim YC
(2009) Cognitive-enhancing activity of loganin isolated
from Cornus officinalis in scopolamine-induced amnesic
mice. Arch Pharm Res 32, 677-683.
Tsai FS, Peng WH, Wang WH, Wu CR, Hsieh CC, Lin YT,
Feng IC, Hsieh MT (2007) Effects of luteolin on learning
acquisition in rats: involvement of the central cholinergic
system. Life Sci 80, 1692-1698.
Tsai FS, Cheng HY, Hsieh MT, Wu CR, Lin YC, Peng
WH (2010) The ameliorating effects of luteolin on betaamyloid-induced impairment of water maze performance
and passive avoidance in rats. Am J Chin Med 38, 279291.
Cheng HY, Hsieh MT, Tsai FS, Wu CR, Chiu CS, Lee MM,
Xu HX, Zhao ZZ, Peng WH (2010) Neuroprotective effect
of luteolin on amyloid beta protein (25-35)-induced toxicity in cultured rat cortical neurons. Phytother Res 24(Suppl
1), S102-S108.
Xu B, Li XX, He GR, Hu JJ, Mu X, Tian S, Du GH (2010)
Luteolin promotes long-term potentiation and improves
cognitive functions in chronic cerebral hypoperfused rats.
Eur J Pharmacol 627, 99-105.
78
[685]
[686]
[687]
[688]
[689]
[690]
[691]
[692]
[693]
[694]
[695]
[696]
[697]
[698]
[699]
[700]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Parachikova A, Green KN, Hendrix C, LaFerla FM (2010)
Formulation of a medical food cocktail for Alzheimer’s
disease: Beneficial effects on cognition and neuropathology in a mouse model of the disease. PLoS One 5,
e14015.
Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick
DL, Reiter RJ, Efthimiopoulos S, Robakis NK (1997)
Melatonin prevents death of neuroblastoma cells exposed
to the Alzheimer amyloid peptide. J Neurosci 17, 16831690.
Pappolla M, Bozner P, Soto C, Shao H, Robakis NK,
Zagorski M, Frangione B, Ghiso J (1998) Inhibition of
Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem
273, 7185-7188.
Pappolla MA, Chyan YJ, Poeggeler B, Frangione B,
Wilson G, Ghiso J, Reiter RJ (2000) An assessment of
the antioxidant and the antiamyloidogenic properties of
melatonin: Implications for Alzheimer’s disease. J Neural
Transm 107, 203-231.
Pappolla MA, Simovich MJ, Bryant-Thomas T, Chyan
YJ, Poeggeler B, Dubocovich M, Bick R, Perry G,
Cruz-Sanchez F, Smith MA (2002) The neuroprotective
activities of melatonin against the Alzheimer beta-protein
are not mediated by melatonin membrane receptors.
J Pineal Res 32, 135-142.
Wang JZ, Wang ZF (2006) Role of melatonin in
Alzheimer-like neurodegeneration. Acta Pharmacol Sin
27, 41-49.
Cheng Y, Feng Z, Zhang QZ, Zhang JT (2006) Beneficial
effects of melatonin in experimental models of Alzheimer
disease. Acta Pharmacol Sin 27, 129-139.
Srinivasan V, Kaur C, Pandi-Perumal S, Brown GM, Cardinali DP (2010) Melatonin and its agonist ramelteon
in Alzheimer’s disease: Possible therapeutic value. Int J
Alzheimers Dis 2011, 741974.
Srinivasan V, Cardinali DP, Srinivasan US, Kaur C, Brown
GM, Spence DW, Hardeland R, Pandi-Perumal SR (2011)
Therapeutic potential of melatonin and its analogs in
Parkinson’s disease: Focus on sleep and neuroprotection.
Ther Adv Neurol Disord 4, 297-317.
Argyriou A, Prast H, Philippu A (1998) Melatonin
facilitates short-term memory. Eur J Pharmacol 349,
159-162.
Bhadania M, Joshi H, Patel P, Kulkarni VH (2012) Protective effect of menthol on beta-amyloid peptide induced
cognitive deficits in mice. Eur J Pharmacol 681, 50-54.
Lemkul JA, Bevan DR (2010) Destabilizing Alzheimer’s
Abeta(42) protofibrils with morin: Mechanistic insights
from molecular dynamics simulations. Biochemistry 49,
3935-3946.
Lemkul JA, Bevan DR (2012) Morin inhibits the early
stages of amyloid beta-peptide aggregation by altering tertiary and quaternary interactions to produce “off-pathway”
structures. Biochemistry 51, 5990-6009.
Gong EJ, Park HR, Kim ME, Piao S, Lee E, Jo DG, Chung
HY, Ha NC, Mattson MP, Lee J (2011) Morin attenuates tau
hyperphosphorylation by inhibiting GSK3beta. Neurobiol
Dis 44, 223-230.
DeToma AS, Choi JS, Braymer JJ, Lim MH (2011)
Myricetin: A naturally occurring regulator of metalinduced amyloid-beta aggregation and neurotoxicity.
Chembiochem 12, 1198-1201.
Jones JR, Lebar MD, Jinwal UK, Abisambra JF, Koren
J III, Blair L, O’Leary JC, Davey Z, Trotter J, Johnson AG, Weeber E, Eckman CB, Baker BJ, Dickey CA
[701]
[702]
[703]
[704]
[705]
[706]
[707]
[708]
[709]
[710]
[711]
[712]
(2011) The diarylheptanoid (+)-aR,11S-myricanol and
two flavones from bayberry (Myrica cerifera) destabilize
the microtubule-associated protein tau. J Nat Prod 74,
38-44.
Maratha SR, Mahadevan N (2012) Memory enhancing
activity of naringin in unstressed and stressed mice: Possible cholinergic and nitriergic modulation. Neurochem Res
37, 2206-2212.
Ono K, Hasegawa K, Yoshiike Y, Takashima A, Yamada
M, Naiki H (2002) Nordihydroguaiaretic acid potently
breaks down pre-formed Alzheimer’s beta-amyloid fibrils
in vitro. J Neurochem 81, 434-440.
Moss MA, Varvel NH, Nichols MR, Reed DK, Rosenberry
TL (2004) Nordihydroguaiaretic acid does not disaggregate beta-amyloid(1-40) protofibrils but does inhibit
growth arising from direct protofibril association. Mol
Pharmacol 66, 592-600.
Bieschke J, Herbst M, Wiglenda T, Friedrich RP, Boeddrich A, Schiele F, Kleckers D, Lopez Del Amo JM,
Gruning BA, Wang Q, Schmidt MR, Lurz R, Anwyl R,
Schnoegl S, Fandrich M, Frank RF, Reif B, Gunther S,
Walsh DM, Wanker EE (2012) Small-molecule conversion
of toxic oligomers to nontoxic beta-sheet-rich amyloid
fibrils. Nat Chem Biol 8, 93-101.
Choi DY, Lee YJ, Lee SY, Lee YM, Lee HH, Choi IS, Oh
KW, Han SB, Nam SY, Hong JT (2012) Attenuation of
scopolamine-induced cognitive dysfunction by obovatol.
Arch Pharm Res 35, 1279-1286.
Choi DY, Lee JW, Peng J, Lee YJ, Han JY, Lee YH, Choi
IS, Han SB, Jung JK, Lee WS, Lee SH, Kwon BM, Oh KW,
Hong JT (2012) Obovatol improves cognitive functions in
animal models for Alzheimer’s disease. J Neurochem 120,
1048-1059.
Choi DY, Lee JW, Lin G, Lee YK, Lee YH, Choi IS,
Han SB, Jung JK, Kim YH, Kim KH, Oh KW, Hong JT,
Lee MS (2012) Obovatol attenuates LPS-induced memory
impairments in mice via inhibition of NF-kappaB signaling pathway. Neurochem Int 60, 68-77.
Choi DY, Lee YJ, Hong JT, Lee HJ (2012) Antioxidant
properties of natural polyphenols and their therapeutic
potentials for Alzheimer’s disease. Brain Res Bull 87, 144153.
Daccache A, Lion C, Sibille N, Gerard M, Slomianny C,
Lippens G, Cotelle P (2011) Oleuropein and derivatives
from olives as Tau aggregation inhibitors. Neurochem Int
58, 700-707.
Yu CJ, Zheng MF, Kuang CX, Huang WD, Yang Q
(2010) Oren-gedoku-to and its constituents with therapeutic potential in Alzheimer’s disease inhibit indoleamine
2, 3-dioxygenase activity in vitro. J Alzheimers Dis 22,
257-266.
Kim DH, Jeon SJ, Son KH, Jung JW, Lee S, Yoon BH,
Choi JW, Cheong JH, Ko KH, Ryu JH (2006) Effect of the
flavonoid, oroxylin A, on transient cerebral hypoperfusioninduced memory impairment in mice. Pharmacol Biochem
Behav 85, 658-668.
Fujiwara H, Tabuchi M, Yamaguchi T, Iwasaki K,
Furukawa K, Sekiguchi K, Ikarashi Y, Kudo Y, Higuchi
M, Saido TC, Maeda S, Takashima A, Hara M,
Yaegashi N, Kase Y, Arai H (2009) A traditional
medicinal herb Paeonia suffruticosa and its active constituent 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose
have potent anti-aggregation effects on Alzheimer’s amyloid beta proteins in vitro and in vivo. J Neurochem 109,
1648-1657.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[713]
[714]
[715]
[716]
[717]
[718]
[719]
[720]
[721]
[722]
[723]
[724]
[725]
[726]
[727]
[728]
Kim HJ, Lee KW, Lee HJ (2007) Protective effects of
piceatannol against beta-amyloid-induced neuronal cell
death. Ann N Y Acad Sci 1095, 473-482.
Liu R, Wu CX, Zhou D, Yang F, Tian S, Zhang
L, Zhang TT, Du GH (2012) Pinocembrin protects
against beta-amyloid-induced toxicity in neurons through
inhibiting receptor for advanced glycation end products
(RAGE)-independent signaling pathways and regulating
mitochondrion-mediated apoptosis. BMC Med 10, 105.
Gazit E (2002) A possible role for pi-stacking in the selfassembly of amyloid fibrils. FASEB J 16, 77-83.
Smid SD, Maag JL, Musgrave IF (2012) Dietary
polyphenol-derived protection against neurotoxic betaamyloid protein: From molecular to clinical. Food Funct
3, 1242-1250.
Xu J, Rong S, Xie B, Sun Z, Deng Q, Wu H, Bao W, Wang
D, Yao P, Huang F, Liu L (2010) Memory impairment in
cognitively impaired aged rats associated with decreased
hippocampal CREB phosphorylation: Reversal by procyanidins extracted from the lotus seedpod. J Gerontol A
Biol Sci Med Sci 65, 933-940.
Xu J, Rong S, Xie B, Sun Z, Deng Q, Bao W, Wang D, Yao
P, Huang F, Liu L (2011) Changes in the nitric oxide system
contribute to effect of procyanidins extracted from the lotus
seedpod ameliorating memory impairment in cognitively
impaired aged rats. Rejuvenation Res 14, 33-43.
Bithu BS, Reddy NR, Prasad SK, Sairam K, Hemalatha
S (2012) Prosopis cineraria: A potential nootropic agent.
Pharm Biol 50, 1241-1247.
Li J, Wang G, Liu J, Zhou L, Dong M, Wang R, Li X,
Li X, Lin C, Niu Y (2010) Puerarin attenuates amyloidbeta-induced cognitive impairment through suppression of
apoptosis in rat hippocampus in vivo. Eur J Pharmacol
649, 195-201.
Wang G, Zhou L, Zhang Y, Dong M, Li X, Liu J, Niu
Y (2011) Implication of the c-Jun-NH2-terminal kinase
pathway in the neuroprotective effect of puerarin against
1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis
in PC-12 cells. Neurosci Lett 487, 88-93.
Xing G, Dong M, Li X, Zou Y, Fan L, Wang X, Cai D,
Li C, Zhou L, Liu J, Niu Y (2011) Neuroprotective effects
of puerarin against beta-amyloid-induced neurotoxicity in
PC12 cells via a PI3K-dependent signaling pathway. Brain
Res Bull 85, 212-218.
Lin F, Xie B, Cai F, Wu G (2012) Protective effect of
Puerarin on beta-amyloid-induced neurotoxicity in rat hippocampal neurons. Arzneimittelforschung 62, 187-193.
Peng QL, Buz’Zard AR, Lau BH (2002) Pycnogenol
protects neurons from amyloid-beta peptide-induced
apoptosis. Brain Res Mol Brain Res 104, 55-65.
Ansari MA, Abdul HM, Joshi G, Opii WO, Butterfield DA
(2009) Protective effect of quercetin in primary neurons
against Abeta(1-42): Relevance to Alzheimer’s disease.
J Nutr Biochem 20, 269-275.
Iuvone T, De FD, Esposito G, D’Amico A, Izzo AA (2006)
The spice sage and its active ingredient rosmarinic acid
protect PC12 cells from amyloid-beta peptide-induced
neurotoxicity. J Pharmacol Exp Ther 317, 1143-1149.
Park DH, Park SJ, Kim JM, Jung WY, Ryu JH (2010)
Subchronic administration of rosmarinic acid, a natural
prolyl oligopeptidase inhibitor, enhances cognitive performances. Fitoterapia 81, 644-648.
Wang SW, Wang YJ, Su YJ, Zhou WW, Yang SG, Zhang
R, Zhao M, Li YN, Zhang ZP, Zhan DW, Liu RT (2012)
Rutin inhibits beta-amyloid aggregation and cytotoxicity,
[729]
[730]
[731]
[732]
[733]
[734]
[735]
[736]
[737]
[738]
[739]
[740]
[741]
79
attenuates oxidative stress, and decreases the production
of nitric oxide and proinflammatory cytokines. Neurotoxicology 33, 482-490.
Papandreou MA, Kanakis CD, Polissiou MG,
Efthimiopoulos S, Cordopatis P, Margarity M, Lamari FN
(2006) Inhibitory activity on amyloid-beta aggregation
and antioxidant properties of Crocus sativus stigmas
extract and its crocin constituents. J Agric Food Chem 54,
8762-8768.
Papandreou MA, Tsachaki M, Efthimiopoulos S, Cordopatis P, Lamari FN, Margarity M (2011) Memory
enhancing effects of saffron in aged mice are correlated
with antioxidant protection. Behav Brain Res 219, 197204.
Akhondzadeh S, Sabet MS, Harirchian MH, Togha M,
Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi MH,
Alimardani R, Jamshidi A, Zare F, Moradi A (2010) Saffron in the treatment of patients with mild to moderate
Alzheimer’s disease: A 16-week, randomized and placebocontrolled trial. J Clin Pharm Ther 35, 581-588.
Akhondzadeh S, Shafiee SM, Harirchian MH, Togha M,
Cheraghmakani H, Razeghi S, Hejazi SS, Yousefi MH, Alimardani R, Jamshidi A, Rezazadeh SA, Yousefi A, Zare
F, Moradi A, Vossoughi A (2010) A 22-week, multicenter, randomized, double-blind controlled trial of Crocus
sativus in the treatment of mild-to-moderate Alzheimer’s
disease. Psychopharmacology (Berl) 207, 637-643.
Geromichalos GD, Lamari FN, Papandreou MA, Trafalis
DT, Margarity M, Papageorgiou A, Sinakos Z (2012) Saffron as a source of novel acetylcholinesterase inhibitors:
Molecular docking and in vitro enzymatic studies. J Agric
Food Chem 60, 6131-6138.
Zhang L, Yu H, Zhao X, Lin X, Tan C, Cao G, Wang Z
(2010) Neuroprotective effects of salidroside against betaamyloid-induced oxidative stress in SH-SY5Y human
neuroblastoma cells. Neurochem Int 57, 547-555.
Ito Y, Kosuge Y, Sakikubo T, Horie K, Ishikawa N,
Obokata N, Yokoyama E, Yamashina K, Yamamoto M,
Saito H, Arakawa M, Ishige K (2003) Protective effect
of S-allyl-L-cysteine, a garlic compound, on amyloid
beta-protein-induced cell death in nerve growth factordifferentiated PC12 cells. Neurosci Res 46, 119-125.
Ito Y, Ito M, Takagi N, Saito H, Ishige K (2003) Neurotoxicity induced by amyloid beta-peptide and ibotenic acid in
organotypic hippocampal cultures: Protection by S-allylL-cysteine, a garlic compound. Brain Res 985, 98-107.
Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T,
Hiramatsu M, Ikejima T, Nabeshima T (2009) Silibinin
prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 157,
1270-1277.
Lee HE, Kim DH, Park SJ, Kim JM, Lee YW, Jung JM,
Lee CH, Hong JG, Liu X, Cai M, Park KJ, Jang DS, Ryu JH
(2012) Neuroprotective effect of sinapic acid in a mouse
model of amyloid beta(1-42) protein-induced Alzheimer’s
disease. Pharmacol Biochem Behav 103, 260-266.
Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG,
Wurtman RJ, Wilkinson D, Twisk JW, Kurz A (2010) Efficacy of a medical food in mild Alzheimer’s disease: A
randomized, controlled trial. Alzheimers Dement 6, 1-10.
Alzheimer Research Forum (2011) Nutrient formulation appears to grease memory function, http://www.
alzforum.org/new/detail.asp?id=2957.
Cummings JL (2012) Food for thought: Souvenaid(R) in
mild Alzheimer’s disease. J Alzheimers Dis 31, 237-238.
80
[742]
[743]
[744]
[745]
[746]
[747]
[748]
[749]
[750]
[751]
[752]
[753]
[754]
[755]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Pieri M, Amadoro G, Carunchio I, Ciotti MT, Quaresima
S, Florenzano F, Calissano P, Possenti R, Zona C, Severini C (2010) SP protects cerebellar granule cells against
beta-amyloid-induced apoptosis by down-regulation and
reduced activity of Kv4 potassium channels. Neuropharmacology 58, 268-276.
Yang EJ, Kim SI, Ku HY, Lee DS, Lee JW, Kim YS, Seong
YH, Song KS (2010) Syringin from stem bark of Fraxinus
rhynchophylla protects Abeta(25-35)-induced toxicity in
neuronal cells. Arch Pharm Res 33, 531-538.
Ono K, Hasegawa K, Naiki H, Yamada M (2004) Antiamyloidogenic activity of tannic acid and its activity
to destabilize Alzheimer’s beta-amyloid fibrils in vitro.
Biochim Biophys Acta 1690, 193-202.
Inbar P, Bautista MR, Takayama SA, Yang J (2008) Assay
to screen for molecules that associate with Alzheimer’s
related beta-amyloid fibrils. Anal Chem 80, 3502-3506.
Mori T, Rezai-Zadeh K, Koyama N, Arendash GW, Yamaguchi H, Kakuda N, Horikoshi-Sakuraba Y, Tan J, Town T
(2012) Tannic acid is a natural beta-secretase inhibitor that
prevents cognitive impairment and mitigates Alzheimerlike pathology in transgenic mice. J Biol Chem 287,
6912-6927.
Yang SG, Wang WY, Ling TJ, Feng Y, Du XT, Zhang
X, Sun XX, Zhao M, Xue D, Yang Y, Liu RT (2010)
alpha-Tocopherol quinone inhibits beta-amyloid aggregation and cytotoxicity, disaggregates preformed fibrils and
decreases the production of reactive oxygen species, NO
and inflammatory cytokines. Neurochem Int 57, 914-922.
Yang ZQ, Yang SF, Yang JQ, Zhou QX, Li SL (2007)
Protective effects and mechanism of total coptis alkaloids
on a beta 25-35 induced learning and memory dysfunction
in rats. Chin J Integr Med 13, 50-54.
Hong SY, Jeong WS, Jun M (2012) Protective effects of the
key compounds isolated from Corni fructus against betaamyloid-induced neurotoxicity in PC12 cells. Molecules
17, 10831-10845.
Takasaki J, Ono K, Yoshiike Y, Hirohata M, Ikeda T,
Morinaga A, Takashima A, Yamada M (2011) Vitamin A
has anti-oligomerization effects on amyloid-beta in vitro.
J Alzheimers Dis 27, 271-280.
Kulkarni SK, Dhir A (2008) Withania somnifera: An
Indian ginseng. Prog Neuropsychopharmacol Biol Psychiatry 32, 1093-1105.
Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel
E, Khanna P, Jain SC, Thakur SS, Ravindranath V (2012)
Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related
protein in liver. Proc Natl Acad Sci U S A 109, 3510-3515.
Wang XM, Fu H, Liu GX, Zhu W, Li L, Yang JX (2007)
Effect of modified wuzi yanzong granule on patients with
mild cognitive impairment from oxidative damage aspect.
Chin J Integr Med 13, 258-263.
Hayashi Y, Ishida Y, Inoue T, Udagawa M, Takeuchi K,
Yoshimuta H, Kiue K, Ninomiya Y, Kawano J, Sameshima
T, Kawahara T, Goto I, Shudo K, Kurayama S, Nakamura J, Okahara K, Mitsuyama Y (2010) Treatment of
behavioral and psychological symptoms of Alzheimertype dementia with Yokukansan in clinical practice. Prog
Neuropsychopharmacol Biol Psychiatry 34, 541-545.
Uchida N, Takasaki K, Sakata Y, Nogami A, Oishi
H, Watanabe T, Shindo T, Egashira N, Kubota K,
Katsurabayashi S, Mishima K, Fujiwara M, Nishimura R,
Iwasaki K (2012) Cholinergic involvement and synaptic
dynamin 1 expression in yokukansan-mediated improve-
[756]
[757]
[758]
[759]
[760]
[761]
[762]
[763]
[764]
[765]
[766]
[767]
[768]
[769]
[770]
[771]
ment of spatial memory in a rat model of early Alzheimer’s
disease. Phytother Res, doi: 10.1002/ptr.4818 [Epub ahead
of print].
Tohda C, Tamura T, Komatsu K (2003) Repair of amyloid
beta(25-35)-induced memory impairment and synaptic
loss by a Kampo formula, Zokumei-to. Brain Res 990,
141-147.
Takahashi K, Matsumura T, Ishihara J, Hatakeyama S
(2007) A highly stereocontrolled total synthesis of dysiherbaine. Chem Commun (Camb) 4158-4160.
Nakanishi K (2005) Terpene trilactones from Gingko
biloba: From ancient times to the 21st century. Bioorg Med
Chem 13, 4987-5000.
Keowkase R, Aboukhatwa M, Adam BL, Beach JW, Terry
AV Jr, Buccafussco JJ, Luo Y (2010) Neuroprotective
effects and mechanism of cognitive-enhancing choline
analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture
and Caenorhabditis elegans. Mol Neurodegener 5, 59.
Sood A, Warren BJ, Webster SJ, Terry AV, Buccafusco JJ
(2007) The effects of JWB1-84-1 on memory-related task
performance by amyloid Abeta transgenic mice and by
young and aged monkeys. Neuropharmacology 53, 588600.
Shin KY, Lee GH, Park CH, Kim HJ, Park SH, Kim S,
Kim HS, Lee KS, Won BY, Lee HG, Choi JH, Suh YH
(2007) A novel compound, maltolyl p-coumarate, attenuates cognitive deficits and shows neuroprotective effects
in vitro and in vivo dementia models. J Neurosci Res 85,
2500-2511.
Guan J, Zhang R, le-Gandar L, Hodgkinson S, Vickers
MH (2010) NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in
the adult rat. Behav Brain Res 210, 221-228.
Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan
M, Shah SM, Burns LH (2012) Reducing amyloid-related
Alzheimer’s disease pathogenesis by a small molecule targeting filamin a. J Neurosci 32, 9773-9784.
Zs-Nagy I, Ohta M, Kitani K (1989) Effect of centrophenoxine and BCE-001 treatment on lateral diffusion of
proteins in the hepatocyte plasma membrane as revealed
by fluorescence recovery after photobleaching in rat liver
smears. Exp Gerontol 24, 317-330.
Zs-Nagy I (1994) A survey of the available data on a new
nootropic drug, BCE-001. Ann N Y Acad Sci 717, 102-114.
Nagy K, Dajko G, Uray I, Zs-Nagy I (1994) Comparative studies on the free radical scavenger properties of two
nootropic drugs, CPH and BCE-001. Ann N Y Acad Sci
717, 115-121.
Scopes D, O’Hare E, Jeggo R, Whyment A, Spanswick D,
Kim EM, Gannon J, Amijee H, Treherne J (2012) Abeta
oligomer toxicity inhibitor protects memory in models of
synaptic toxicity. Br J Pharmacol 167, 383-392.
Pierce JE, Smith DH, Eison MS, McIntosh TK (1993) The
nootropic compound BMY-21502 improves spatial learning ability in brain injured rats. Brain Res 624, 199-208.
Saletu B, Schulz H, Herrmann WM, Anderer P, Shrotriya
RC, Vanbrabant E (1994) BMS-181168 for protection of
the human brain against hypoxia: Double-blind, placebocontrolled EEG mapping studies. Pharmacopsychiatry 27,
189-197.
Shrotriya RC, Cutler NR, Sramek JJ, Veroff AE, Hironaka DY (1996) Efficacy and safety of BMY 21,502 in
Alzheimer disease. Ann Pharmacother 30, 1376-1380.
Lishko PV, Maximyuk OP, Chatterjee SS, Noldner M,
Krishtal OA (1998) The putative cognitive enhancer KA-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[772]
[773]
[774]
[775]
[776]
[777]
[778]
[779]
[780]
[781]
[782]
[783]
[784]
[785]
[786]
[787]
672.HCl is an uncompetitive voltage-dependent NMDA
receptor antagonist. Neuroreport 9, 4193-4197.
Sourgens H, Hoerr R, Biber A, Steinbrede H, Derendorf H
(1998) KA 672-HCl, a neuronal activator against dementia: Tolerability, safety, and preliminary pharmacokinetics
after single and multiple oral doses in healthy male and
female volunteers. J Clin Pharmacol 38, 373-381.
Winter JC, Helsley SE, Rabin RA (1998) The discriminative stimulus effects of KA 672, a putative cognitive
enhancer: Evidence for a 5-HT1A component. Pharmacol
Biochem Behav 60, 703-707.
Reisner E, Noldner M, Rossner S, Chatterjee SS, Bigl V,
Schliebs R (1999) Acute effect of KA-672, a putative cognitive enhancer, on neurotransmitter receptor binding in
mouse brain. Neurosci Lett 274, 187-190.
Teismann P, Ferger B (2000) In vivo effects of the putative
cognitive enhancer KA-672.HCl in comparison with 8hydroxy-2-(di-N-propylamino) tetralin and haloperidol on
dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and
5-hydroxyindoleacetic acid levels in striatal and cortical
brain regions. Prog Neuropsychopharmacol Biol Psychiatry 24, 337-348.
Teismann P, Ferger B (2000) Effects of ensaculin on
dopamine metabolite levels and K(+)-induced glutamate
release. Eur J Pharmacol 398, 247-250.
Hoerr R, Noeldner M (2002) Ensaculin (KA-672 HCl):
a multitransmitter approach to dementia treatment. CNS
Drug Rev 8, 143-158.
Sramek JJ, Cutler NR (2000) Ongoing trials in Alzheimer’s
disease. Expert Opin Investig Drugs 9, 899-915.
Inozemtsev AN, Garibova TL, Khromova IV, Alvarez R,
Voronina TA, Tushmalova NA (1993) [The effect of nooglutil and piracetam on different forms of operant learning].
Eksp Klin Farmakol 56, 6-8.
Mondadori C, Ducret T, Borkowski J (1991) How long
does ‘memory consolidation’ take? New compounds can
improve retention performance, even if administered up
to 24 hours after the learning experience. Brain Res 555,
107-111.
Mondadori C, Buerki H, Borkowski J, Radeke E, Ducret
T, Glatt A (1992) CGS 5649 B, a new compound, reverses
age-related cognitive dysfunctions in rats. Behav Neural
Biol 57, 149-156.
Nilsson E, Schneider T, Hoffmann E, Schmidt EK (1991)
Urinary excretion of CGS 5,649 and its conjugated
glucuronide and sulfate in man. Eur J Drug Metab Pharmacokinet Spec No 3, 201-204.
Molloy DW, Guyatt GH, Standish T, Willan A, McIlroy
W, D’Souza J, Brown G, Mondadori C (1993) Effect of a
new nootropic agent, CGS 5649B, on cognition, function,
and behavior in dementia. J Gen Intern Med 8, 444-447.
Clincke GH, Tritsmans L, Idzikowski C, Amery WK,
Janssen PA (1988) The effect of R 58 735 (Sabeluzole)
on memory functions in healthy elderly volunteers. Psychopharmacology (Berl) 94, 52-57.
Clincke GH, Tritsmans L (1988) Sabeluzole (R58 735)
increases consistent retrieval during serial learning and
relearning of nonsense syllables. Psychopharmacology
(Berl) 96, 309-310.
Tritsmans L, Clincke G, Amery WK (1988) The effect
of sabeluzole (R 58735) on memory retrieval functions.
Psychopharmacology (Berl) 94, 527-531.
Geerts H, Nuydens R, Nuyens R, Cornelissen F (1992)
Sabeluzole accelerates neurite outgrowth in different neuronal cell lines. Restor Neurol Neurosci 4, 21-32.
[788]
[789]
[790]
[791]
[792]
[793]
[794]
[795]
[796]
[797]
[798]
[799]
[800]
[801]
[802]
[803]
81
Geerts H, Nuydens R, Nuyens R, Cornelissen F, De BM,
Pauwels P, Janssen PA, Song YH, Mandelkow EM (1992)
Sabeluzole, a memory-enhancing molecule, increases fast
axonal transport in neuronal cell cultures. Exp Neurol 117,
36-43.
Geerts H, Nuydens R, de JM, Cornelissen F, Nuyens
R, Wouters L (1996) Sabeluzole stabilizes the neuronal
cytoskeleton. Neurobiol Aging 17, 573-581.
Wong YN, Quon CY, Holm KA, Burcham DL, Frey
NL, Huang SM, Lam GN (1996) Pharmacokinetics and
metabolism of EXP921, a novel cognitive enhancer, in rats.
Drug Metab Dispos 24, 172-179.
Saletu B, Semlitsch HV, Anderer P, Resch F, Presslich
O, Schuster P (1989) Psychophysiological research in
psychiatry and neuropsychopharmacology. II. The investigation of antihypoxidotic/nootropic drugs (tenilsetam and
co-dergocrine-mesylate) in elderlies with the Viennese
Psychophysiological Test-System (VPTS). Methods Find
Exp Clin Pharmacol 11, 43-55.
Webster J, Urban C, Berbaum K, Loske C, Alpar A,
Gartner U, de Arriba SG, Arendt T, Munch G (2005)
The carbonyl scavengers aminoguanidine and tenilsetam
protect against the neurotoxic effects of methylglyoxal.
Neurotox Res 7, 95-101.
Rainer M, Brunnbauer M, Dunky A, Ender F, Goldsteiner
H, Holl O, Kotlan P, Paulitsch G, Reiner C, Stossl J,
Zachhuber C, Mossler H (1997) Therapeutic results with
Cerebrolysin in the treatment of dementia. Wien Med
Wochenschr 147, 426-431.
Xiong H, Baskys A, Wojtowicz JM (1996) Brain-derived
peptides inhibit synaptic transmission via presynaptic
GABAB receptors in CA1 area of rat hippocampal slices.
Brain Res 737, 188-194.
Kofler B, Erhart C, Erhart P, Harrer G (1990) A multidimensional approach in testing nootropic drug effects
(Cerebrolysin). Arch Gerontol Geriatr 10, 129-140.
Hutter-Paier B, Eggenreich U, Windisch M (1996)
Effects of two protein-free peptide derivatives on passive
avoidance behaviour of 24-month-old rats. Arzneimittelforschung 46, 237-241.
Hutter-Paier B, Eggenreich U, Windisch M (1996) Dosedependent behavioural effects of two protein-free peptide
derivatives on the passive avoidance reaction of rats.
Arzneimittelforschung 46, 242-246.
Gschanes A, Windisch M (1996) The influence of cerebrolysin and E021 on spatial navigation of young rats. J
Neural Transm Suppl 47, 278.
Gschanes A, Windisch M (1998) The influence of Cerebrolysin and E021 on spatial navigation of 24-month-old
rats. J Neural Transm Suppl 53, 313-321.
Hutter-Paier B, Fruhwirth M, Grygar E, Windisch M
(1996) Cerebrolysin protects neurons from ischemiainduced loss of microtubule–associated protein 2. J Neural
Transm Suppl 47, 276.
Rockenstein E, Mallory M, Mante M, Alford M, Windisch
M, Moessler H, Masliah E (2002) Effects of Cerebrolysin
on amyloid-beta deposition in a transgenic model of
Alzheimer’s disease. J Neural Transm Suppl 62, 327-336.
Rockenstein E, Adame A, Mante M, Moessler H, Windisch
M, Masliah E (2003) The neuroprotective effects of Cerebrolysin in a transgenic model of Alzheimer’s disease are
associated with improved behavioral performance. J Neural Transm 110, 1313-1327.
Rockenstein E, Adame A, Mante M, Larrea G, Crews L,
Windisch M, Moessler H, Masliah E (2005) Ameliora-
82
[804]
[805]
[806]
[807]
[808]
[809]
[810]
[811]
[812]
[813]
[814]
[815]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
tion of the cerebrovascular amyloidosis in a transgenic
model of Alzheimer’s disease with the neurotrophic
compound cerebrolysin. J Neural Transm 112, 269282.
Rockenstein E, Torrance M, Mante M, Adame A, Paulino
A, Rose JB, Crews L, Moessler H, Masliah E (2006)
Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic
model of Alzheimer’s disease. J Neurosci Res 83, 12521261.
Rockenstein E, Mante M, Adame A, Crews L, Moessler H,
Masliah E (2007) Effects of Cerebrolysin on neurogenesis
in an APP transgenic model of Alzheimer’s disease. Acta
Neuropathol 113, 265-275.
Rockenstein E, Ubhi K, Pham E, Michael S, Doppler E,
Novak P, Inglis C, Mante M, Adame A, Alvarez XA,
Moessler H, Masliah E (2011) Beneficial effects of a
neurotrophic peptidergic mixture persist for a prolonged
period following treatment interruption in a transgenic
model of Alzheimer’s disease. J Neurosci Res 89, 18121821.
Rockenstein E, Ubhi K, Doppler E, Novak P, Moessler H,
Li B, Blanchard J, Grundke-Iqbal I, Iqbal K, Mante M,
Adame A, Crews L, Masliah E (2011) Regional comparison of the neurogenic effects of CNTF-derived peptides
and cerebrolysin in AbetaPP transgenic mice. J Alzheimers
Dis 27, 743-752.
Masliah E, Diez-Tejedor E (2012) The pharmacology
of neurotrophic treatment with Cerebrolysin: Brain protection and repair to counteract pathologies of acute
and chronic neurological disorders. Drugs Today (Barc)
48(Suppl A), 3-24.
Panisset M, Gauthier S, Moessler H, Windisch M (2002)
Cerebrolysin in Alzheimer’s disease: A randomized,
double-blind, placebo-controlled trial with a neurotrophic
agent. J Neural Transm 109, 1089-1104.
Molloy DW, Standish TI (2000) Clinical experience with
Cerebrolysin. J Neural Transm Suppl 59, 293-300.
Ruether E, Alvarez XA, Rainer M, Moessler H (2002)
Sustained improvement of cognition and global function
in patients with moderately severe Alzheimer’s disease:
A double-blind, placebo-controlled study with the neurotrophic agent Cerebrolysin. J Neural Transm Suppl 62,
265-275.
Ladurner G, Kalvach P, Moessler H (2005) Neuroprotective treatment with cerebrolysin in patients with acute
stroke: A randomised controlled trial. J Neural Transm
112, 415-428.
Alvarez XA, Cacabelos R, Laredo M, Couceiro V, Sampedro C, Varela M, Corzo L, Fernandez-Novoa L, Vargas
M, Aleixandre M, Linares C, Granizo E, Muresanu D,
Moessler H (2006) A 24-week, double-blind, placebocontrolled study of three dosages of Cerebrolysin in
patients with mild to moderate Alzheimer’s disease. Eur J
Neurol 13, 43-54.
Alvarez XA, Sampedro C, Figueroa J, Tellado I, Gonzalez A, Garcia-Fantini M, Cacabelos R, Muresanu D,
Moessler H (2008) Reductions in qEEG slowing over 1
year and after treatment with Cerebrolysin in patients with
moderate-severe traumatic brain injury. J Neural Transm
115, 683-692.
Alvarez XA, Sampedro C, Cacabelos R, Linares C,
Aleixandre M, Garcia-Fantini M, Moessler H (2009)
Reduced TNF-alpha and increased IGF-I levels in the
serum of Alzheimer’s disease patients treated with the neu-
[816]
[817]
[818]
[819]
[820]
[821]
[822]
[823]
[824]
[825]
[826]
[827]
[828]
[829]
[830]
rotrophic agent cerebrolysin. Int J Neuropsychopharmacol
12, 867-872.
Alvarez XA, Cacabelos R, Sampedro C, Aleixandre M,
Linares C, Granizo E, Doppler E, Moessler H (2011)
Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer’s disease: Results of a randomized,
double-blind, controlled trial investigating three dosages
of Cerebrolysin. Eur J Neurol 18, 59-68.
Muresanu DF, Alvarez XA, Moessler H, Buia M, Stan A,
Pintea D, Moldovan F, Popescu BO (2008) A pilot study to
evaluate the effects of Cerebrolysin on cognition and qEEG
in vascular dementia: Cognitive improvement correlates
with qEEG acceleration. J Neurol Sci 267, 112-119.
Muresanu DF, Alvarez XA, Moessler H, Novak PH, Stan
A, Buzoianu A, Bajenaru O, Popescu BO (2010) Persistence of the effects of Cerebrolysin on cognition and
qEEG slowing in vascular dementia patients: Results of a
3-month extension study. J Neurol Sci 299, 179-183.
Plosker GL, Gauthier S (2009) Cerebrolysin: A review of
its use in dementia. Drugs Aging 26, 893-915.
Plosker GL, Gauthier S (2010) Spotlight on cerebrolysin
in dementia. CNS Drugs 24, 263-266.
Bajenaru O, Tiu C, Moessler H, Antochi F, Muresanu D,
Popescu BO, Novak P (2010) Efficacy and safety of Cerebrolysin in patients with hemorrhagic stroke. J Med Life
3, 137-143.
Guekht AB, Moessler H, Novak PH, Gusev EI (2011)
Cerebrolysin in vascular dementia: Improvement of
clinical outcome in a randomized, double-blind, placebocontrolled multicenter trial. J Stroke Cerebrovasc Dis 20,
310-318.
Allegri RF, Guekht A (2012) Cerebrolysin improves symptoms and delays progression in patients with Alzheimer’s
disease and vascular dementia. Drugs Today (Barc) 48
Suppl A, 25-41.
Alvarez XA, Cacabelos R, Sampedro C, Couceiro V,
Aleixandre M, Vargas M, Linares C, Granizo E, GarciaFantini M, Baurecht W, Doppler E, Moessler H (2011)
Combination treatment in Alzheimer’s disease: Results
of a randomized, controlled trial with cerebrolysin and
donepezil. Curr Alzheimer Res 8, 583-591.
Anton Alvarez X, Fuentes P (2011) Cerebrolysin in
Alzheimer’s disease. Drugs Today (Barc) 47, 487-513.
Thome J, Doppler E (2012) Safety profile of Cerebrolysin:
Clinical experience from dementia and stroke trials. Drugs
Today (Barc)48 Suppl A, 63-69.
Leker RR, Teichner A, Grigoriadis N, Ovadia H, Brenneman DE, Fridkin M, Giladi E, Romano J, Gozes I
(2002) NAP, a femtomolar-acting peptide, protects the
brain against ischemic injury by reducing apoptotic death.
Stroke 33, 1085-1092.
Ashur-Fabian O, Segal-Ruder Y, Skutelsky E, Brenneman
DE, Steingart RA, Giladi E, Gozes I (2003) The neuroprotective peptide NAP inhibits the aggregation of the
beta-amyloid peptide. Peptides 24, 1413-1423.
Alcalay RN, Giladi E, Pick CG, Gozes I (2004)
Intranasal administration of NAP, a neuroprotective peptide, decreases anxiety-like behavior in aging mice in the
elevated plus maze. Neurosci Lett 361, 128-131.
Gozes I, Zaltzman R, Hauser J, Brenneman DE, Shohami
E, Hill JM (2005) The expression of activity-dependent
neuroprotective protein (ADNP) is regulated by brain damage and treatment of mice with the ADNP derived peptide,
NAP, reduces the severity of traumatic head injury. Curr
Alzheimer Res 2, 149-153.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[831]
[832]
[833]
[834]
[835]
[836]
[837]
[838]
[839]
[840]
[841]
[842]
[843]
[844]
[845]
[846]
Matsuoka Y, Gray AJ, Hirata-Fukae C, Minami SS, Waterhouse EG, Mattson MP, LaFerla FM, Gozes I, Aisen PS
(2007) Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in
a transgenic mouse model of Alzheimer’s disease at early
pathological stage. J Mol Neurosci 31, 165-170.
Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae
C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio
O, Gozes I, Aisen PS (2008) A neuronal microtubuleinteracting agent, NAPVSIPQ, reduces tau pathology
and enhances cognitive function in a mouse model of
Alzheimer’s disease. J Pharmacol Exp Ther 325, 146-153.
Shiryaev N, Jouroukhin Y, Giladi E, Polyzoidou E, Grigoriadis NC, Rosenmann H, Gozes I (2009) NAP protects
memory, increases soluble tau and reduces tau hyperphosphorylation in a tauopathy model. Neurobiol Dis 34,
381-388.
Gozes I, Divinski I (2004) The femtomolar-acting NAP
interacts with microtubules: Novel aspects of astrocyte
protection. J Alzheimers Dis 6, S37-S41.
Gozes I, Divinski I (2007) NAP, a neuroprotective drug
candidate in clinical trials, stimulates microtubule assembly in the living cell. Curr Alzheimer Res 4, 507-509.
Merenlender-Wagner A, Pikman R, Giladi E, Andrieux
A, Gozes I (2010) NAP (davunetide) enhances cognitive
behavior in the STOP heterozygous mouse–a microtubuledeficient model of schizophrenia. Peptides 31, 1368-1373.
Fleming SM, Mulligan CK, Richter F, Mortazavi F,
Lemesre V, Frias C, Zhu C, Stewart A, Gozes I, Morimoto B, Chesselet MF (2011) A pilot trial of the
microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor
function and reduction of alpha-synuclein inclusions. Mol
Cell Neurosci 46, 597-606.
Gozes I (2007) Activity-dependent neuroprotective protein: From gene to drug candidate. Pharmacol Ther 114,
146-154.
Gozes I (2011) NAP (davunetide) provides functional and
structural neuroprotection. Curr Pharm Des 17, 10401044.
Gozes I (2011) Microtubules, schizophrenia and cognitive
behavior: Preclinical development of davunetide (NAP) as
a peptide-drug candidate. Peptides 32, 428-431.
Gozes I (2011) Microtubules (tau) as an emerging therapeutic target: NAP (davunetide). Curr Pharm Des 17,
3413-3417.
Gozes I, Spivak-Pohis I (2006) Neurotrophic effects of
the peptide NAP: A novel neuroprotective drug candidate.
Curr Alzheimer Res 3, 197-199.
Gozes I, Steingart RA, Spier AD (2004) NAP mechanisms
of neuroprotection. J Mol Neurosci 24, 67-72.
Gozes I, Morimoto BH, Tiong J, Fox A, Sutherland K,
Dangoor D, Holser-Cochav M, Vered K, Newton P, Aisen
PS, Matsuoka Y, van Dyck CH, Thal L (2005) NAP:
Research and development of a peptide derived from
activity-dependent neuroprotective protein (ADNP). CNS
Drug Rev 11, 353-368.
Gozes I, Stewart A, Morimoto B, Fox A, Sutherland
K, Schmeche D (2009) Addressing Alzheimer’s disease
tangles: From NAP to AL-108. Curr Alzheimer Res 6,
455-460.
Geerts H (2008) AL-108 and AL-208, formulations of the
neuroprotective NAP fragment of activity-dependent neuroprotective protein, for cognitive disorders. Curr Opin
Investig Drugs 9, 800-811.
[847]
[848]
[849]
[850]
[851]
[852]
[853]
[854]
[855]
[856]
[857]
[858]
[859]
[860]
[861]
[862]
83
Shiryaev N, Pikman R, Giladi E, Gozes I (2011) Protection
against tauopathy by the drug candidates NAP (davunetide) and D-SAL: Biochemical, cellular and behavioral
aspects. Curr Pharm Des 17, 2603-2612.
Javitt DC, Buchanan RW, Keefe RS, Kern R, McMahon
RP, Green MF, Lieberman J, Goff DC, Csernansky JG,
McEvoy JP, Jarskog F, Seidman LJ, Gold JM, Kimhy
D, Nolan KS, Barch DS, Ball MP, Robinson J, Marder
SR (2012) Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in
schizophrenia. Schizophr Res 136, 25-31.
Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M,
Schorderet DF, Bogousslavsky J, Bonny C (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against
excitotoxicity and cerebral ischemia. Nat Med 9, 11801186.
Hirt L, Badaut J, Thevenet J, Granziera C, Regli L, Maurer F, Bonny C, Bogousslavsky J (2004) D-JNKI1, a
cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia. Stroke
35, 1738-1743.
Suckfuell M, Canis M, Strieth S, Scherer H, Haisch A
(2007) Intratympanic treatment of acute acoustic trauma
with a cell-permeable JNK ligand: A prospective randomized phase I/II study. Acta Otolaryngol 127, 938-942.
Wiegler K, Bonny C, Coquoz D, Hirt L (2008) The JNK
inhibitor XG-102 protects from ischemic damage with
delayed intravenous administration also in the presence
of recombinant tissue plasminogen activator. Cerebrovasc
Dis 26, 360-366.
Tayal V, Kalra BS (2008) Cytokines and anti-cytokines as
therapeutics–an update. Eur J Pharmacol 579, 1-12.
Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP
(2008) Tumor necrosis factor antagonist mechanisms of
action: A comprehensive review. Pharmacol Ther 117,
244-279.
Tobinick EL (2007) Perispinal etanercept for the treatment
of Alzheimer’s disease. Curr Alzheimer Res 4, 550-552.
Tobinick EL, Gross H (2008) Rapid improvement in verbal fluency and aphasia following perispinal etanercept in
Alzheimer’s disease. BMC Neurol 8, 27.
Tobinick EL, Gross H (2008) Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration. J Neuroinflammation 5, 2.
Griffin WS (2008) Perispinal etanercept: Potential as an
Alzheimer therapeutic. J Neuroinflammation 5, 3.
Sara VR, Carlsson-Skwirut C, Bergman T, Jornvall H,
Roberts PJ, Crawford M, Hakansson LN, Civalero I, Nordberg A (1989) Identification of Gly-Pro-Glu (GPE), the
aminoterminal tripeptide of insulin-like growth factor 1
which is truncated in brain, as a novel neuroactive peptide.
Biochem Biophys Res Commun 165, 766-771.
Sara VR, Carlsson-Skwirut C, Drakenberg K, Giacobini
MB, Hakansson L, Mirmiran M, Nordberg A, Olson L,
Reinecke M, Stahlbom PA (1993) The biological role of
truncated insulin-like growth factor-1 and the tripeptide
GPE in the central nervous system. Ann N Y Acad Sci 692,
183-191.
Saura J, Curatolo L, Williams CE, Gatti S, Benatti L,
Peeters C, Guan J, Dragunow M, Post C, Faull RL, Gluckman PD, Skinner SJ (1999) Neuroprotective effects of
Gly-Pro-Glu, the N-terminal tripeptide of IGF-1, in the
hippocampus in vitro. Neuroreport 10, 161-164.
Aguado-Llera D, Martin-Martinez M, Garcia-Lopez MT,
rilla-Ferreiro E, Barrios V (2004) Gly-Pro-Glu protects
84
[863]
[864]
[865]
[866]
[867]
[868]
[869]
[870]
[871]
[872]
[873]
[874]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
beta-amyloid-induced somatostatin depletion in the rat
cortex. Neuroreport 15, 1979-1982.
Burgos-Ramos E, Martos-Moreno GA, Lopez MG,
Herranz R, Aguado-Llera D, Egea J, Frechilla D, Cenarruzabeitia E, Leon R, Arilla-Ferreiro E, Argente J, Barrios
V (2009) The N-terminal tripeptide of insulin-like growth
factor-I protects against beta-amyloid-induced somatostatin depletion by calcium and glycogen synthase kinase
3 beta modulation. J Neurochem 109, 360-370.
Bickerdike MJ, Thomas GB, Batchelor DC, Sirimanne
ES, Leong W, Lin H, Sieg F, Wen J, Brimble MA, Harris PW, Gluckman PD (2009) NNZ-2566: A Gly-Pro-Glu
analogue with neuroprotective efficacy in a rat model of
acute focal stroke. J Neurol Sci 278, 85-90.
Lu XC, Chen RW, Yao C, Wei H, Yang X, Liao Z, Dave
JR, Tortella FC (2009) NNZ-2566, a glypromate analog,
improves functional recovery and attenuates apoptosis and
inflammation in a rat model of penetrating ballistic-type
brain injury. J Neurotrauma 26, 141-154.
Lu XC, Si Y, Williams AJ, Hartings JA, Gryder D, Tortella
FC (2009) NNZ-2566, a glypromate analog, attenuates
brain ischemia-induced non-convulsive seizures in rats.
J Cereb Blood Flow Metab 29, 1924-1932.
Wei HH, Lu XC, Shear DA, Waghray A, Yao C, Tortella
FC, Dave JR (2009) NNZ-2566 treatment inhibits neuroinflammation and pro-inflammatory cytokine expression
induced by experimental penetrating ballistic-like brain
injury in rats. J Neuroinflammation 6, 19.
Alonso De Diego SA, Munoz P, Gonzalez-Muniz R, Herranz R, Martin-Martinez M, Cenarruzabeitia E, Frechilla
D, Del RJ, Jimeno ML, Garcia-Lopez MT (2005) Analogues of the neuroprotective tripeptide Gly-Pro-Glu
(GPE): Synthesis and structure-activity relationships.
Bioorg Med Chem Lett 15, 2279-2283.
Alonso De Diego SA, Gutierrez-Rodriguez M, Perez d
V, Casabona D, Cativiela C, Gonzalez-Muniz R, Herranz R, Cenarruzabeitia E, Frechilla D, Del RJ, Jimeno
ML, Garcia-Lopez MT (2006) New Gly-Pro-Glu (GPE)
analogues: Expedite solid-phase synthesis and biological
activity. Bioorg Med Chem Lett 16, 1392-1396.
Alonso De Diego SA, Gutierrez-Rodriguez M, Perez d
V, Gonzalez-Muniz R, Herranz R, Martin-Martinez M,
Cenarruzabeitia E, Frechilla D, Del RJ, Jimeno ML,
Garcia-Lopez MT (2006) The neuroprotective activity of
GPE tripeptide analogues does not correlate with glutamate receptor binding affinity. Bioorg Med Chem Lett 16,
3396-3400.
Lai MY, Brimble MA, Callis DJ, Harris PW, Levi MS,
Sieg F (2005) Synthesis and pharmacological evaluation
of glycine-modified analogues of the neuroprotective agent
glycyl-L-prolyl-L-glutamic acid (GPE). Bioorg Med Chem
13, 533-548.
Holtje M, Djalali S, Hofmann F, Munster-Wandowski A,
Hendrix S, Boato F, Dreger SC, Grosse G, Henneberger
C, Grantyn R, Just I, Ahnert-Hilger G (2009) A 29amino acid fragment of Clostridium botulinum C3 protein
enhances neuronal outgrowth, connectivity, and reinnervation. FASEB J 23, 1115-1126.
Boato F, Hendrix S, Huelsenbeck SC, Hofmann F, Grosse
G, Djalali S, Klimaschewski L, Auer M, Just I, hnertHilger G, Holtje M (2010) C3 peptide enhances recovery
from spinal cord injury by improved regenerative growth
of descending fiber tracts. J Cell Sci 123, 1652-1662.
Just I, Rohrbeck A, Huelsenbeck SC, Hoeltje M (2011)
Therapeutic effects of Clostridium botulinum C3 exoen-
[875]
[876]
[877]
[878]
[879]
[880]
[881]
[882]
[883]
[884]
[885]
[886]
[887]
[888]
[889]
zyme. Naunyn Schmiedebergs Arch Pharmacol 383,
247-252.
Loske P, Boato F, Hendrix S, Piepgras J, Just I, hnertHilger G, Holtje M (2012) Minimal essential length of
Clostridium botulinum C3 peptides to enhance neuronal
regenerative growth and connectivity in a non-enzymatic
mode. J Neurochem 120, 1084-1096.
Jiang Y, Brody DL (2012) Administration of COG1410
reduces axonal amyloid precursor protein immunoreactivity and microglial activation after controlled cortical
impact in mice. J Neurotrauma 29, 2332-2341.
Ghosal K, Stathopoulos A, Thomas D, Phenis D, Vitek
MP, Pimplikar SW (2012) The apolipoprotein-E-mimetic
COG112 protects amyloid precursor protein intracellular domain-overexpressing animals from Alzheimer’s
disease-like pathological features. Neurodegener Dis,
DOI: 10.1159-000341299 [Epub ahead of print].
Corneveaux JJ, Liang WS, Reiman EM, Webster JA,
Myers AJ, Zismann VL, Joshipura KD, Pearson JV, HuLince D, Craig DW, Coon KD, Dunckley T, Bandy D, Lee
W, Chen K, Beach TG, Mastroeni D, Grover A, Ravid R,
Sando SB, Aasly JO, Heun R, Jessen F, Kolsch H, Rogers
J, Hutton ML, Melquist S, Petersen RC, Alexander GE,
Caselli RJ, Papassotiropoulos A, Stephan DA, Huentelman
MJ (2010) Evidence for an association between KIBRA
and late-onset Alzheimer’s disease. Neurobiol Aging 31,
901-909.
Hofmann SG, Smits JA, Asnaani A, Gutner CA, Otto MW
(2011) Cognitive enhancers for anxiety disorders. Pharmacol Biochem Behav 99, 275-284.
Marwarha G, Dasari B, Prasanthi JR, Schommer J, Ghribi
O (2010) Leptin reduces the accumulation of Abeta and
phosphorylated tau induced by 27-hydroxycholesterol in
rabbit organotypic slices. J Alzheimers Dis 19, 1007-1019.
Marwarha G, Dasari B, Prabhakara JP, Schommer J, Ghribi
O (2010) beta-Amyloid regulates leptin expression and tau
phosphorylation through the mTORC1 signaling pathway.
J Neurochem 115, 373-384.
Marwarha G, Prasanthi JR, Schommer J, Dasari B, Ghribi
O (2011) Molecular interplay between leptin, insulin-like
growth factor-1, and beta-amyloid in organotypic slices
from rabbit hippocampus. Mol Neurodegener 6, 41.
Harvey J, Shanley LJ, O’Malley D, Irving AJ (2005) Leptin: A potential cognitive enhancer? Biochem Soc Trans
33, 1029-1032.
Farr SA, Banks WA, Morley JE (2006) Effects of leptin on
memory processing. Peptides 27, 1420-1425.
Beccano-Kelly D, Harvey J (2012) Leptin: A novel therapeutic target in Alzheimer’s disease? Int J Alzheimers Dis
2012, 594137.
Perez-Gonzalez R, Antequera D, Vargas T, Spuch C, Bolos
M, Carro E (2011) Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of
Alzheimer’s disease. J Alzheimers Dis 24(Suppl 2), 17-25.
Lourenco FC, Galvan V, Fombonne J, Corset V, Llambi
F, Muller U, Bredesen DE, Mehlen P (2009) Netrin-1
interacts with amyloid precursor protein and regulates
amyloid-beta production. Cell Death Differ 16, 655-663.
Rama N, Goldschneider D, Corset V, Lambert J, Pays
L, Mehlen P (2012) Amyloid precursor protein regulates
netrin-1-mediated commissural axon outgrowth. J Biol
Chem 287, 30014-30023.
Gorba T, Bradoo P, Antonic A, Marvin K, Liu DX, Lobie
PE, Reymann KG, Gluckman PD, Sieg F (2006) Neural regeneration protein is a novel chemoattractive and
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[890]
[891]
[892]
[893]
[894]
[895]
[896]
[897]
[898]
[899]
[900]
[901]
[902]
[903]
[904]
[905]
neuronal survival-promoting factor. Exp Cell Res 312,
3060-3074.
Xue D, Zhao M, Wang YJ, Wang L, Yang Y, Wang
SW, Zhang R, Zhao Y, Liu RT (2012) A multifunctional
peptide rescues memory deficits in Alzheimer’s disease
transgenic mice by inhibiting Abeta42-induced cytotoxicity and increasing microglial phagocytosis. Neurobiol Dis
46, 701-709.
Schuster D, Rajendran A, Hui SW, Nicotera T, Srikrishnan
T, Kruzel ML (2005) Protective effect of colostrinin on
neuroblastoma cell survival is due to reduced aggregation
of beta-amyloid. Neuropeptides 39, 419-426.
Bourhim M, Kruzel M, Srikrishnan T, Nicotera T (2007)
Linear quantitation of Abeta aggregation using Thioflavin
T: Reduction in fibril formation by colostrinin. J Neurosci
Methods 160, 264-268.
Froud KE, Wardhaugh T, Banks D, Saffrey MJ, Stewart
MG (2010) Colostrinin alleviates amyloid-beta induced
toxicity in rat primary hippocampal cultures. J Alzheimers
Dis 20, 423-426.
Popik P, Bobula B, Janusz M, Lisowski J, Vetulani J (1999)
Colostrinin, a polypeptide isolated from early milk, facilitates learning and memory in rats. Pharmacol Biochem
Behav 64, 183-189.
Stewart MG, Banks D (2006) Enhancement of long-term
memory retention by Colostrinin in one-day-old chicks
trained on a weak passive avoidance learning paradigm.
Neurobiol Learn Mem 86, 66-71.
Szaniszlo P, German P, Hajas G, Saenz DN, Woodberry
MW, Kruzel ML, Boldogh I (2009) Effects of Colostrinin
on gene expression-transcriptomal network analysis. Int
Immunopharmacol 9, 181-193.
Leszek J, Inglot AD, Janusz M, Byczkiewicz F, Kiejna A,
Georgiades J, Lisowski J (2002) Colostrinin proline-rich
polypeptide complex from ovine colostrum–a long-term
study of its efficacy in Alzheimer’s disease. Med Sci Monit
8, I93-I96.
Bilikiewicz A, Gaus W (2004) Colostrinin (a naturally
occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer’s disease. J Alzheimers Dis 6, 17-26.
Boldogh I, Kruzel ML (2008) Colostrinintrade mark: An
oxidative stress modulator for prevention and treatment of
age-related disorders. J Alzheimers Dis 13, 303-321.
Szaniszlo P, German P, Hajas G, Saenz DN, Kruzel M,
Boldogh I (2009) New insights into clinical trial for
Colostrinin in Alzheimer’s disease. J Nutr Health Aging
13, 235-241.
Janusz M, Zablocka A (2010) Colostral proline-rich
polypeptides–immunoregulatory properties and prospects
of therapeutic use in Alzheimer’s disease. Curr Alzheimer
Res 7, 323-333.
Stewart MG (2008) Colostrinin: A naturally occurring
compound derived from mammalian colostrum with efficacy in treatment of neurodegenerative diseases, including
Alzheimer’s. Expert Opin Pharmacother 9, 2553-2559.
Zimecki M (2008) A proline-rich polypeptide from ovine
colostrum: Colostrinin with immunomodulatory activity.
Adv Exp Med Biol 606, 241-250.
Taddei K, Laws SM, Verdile G, Munns S, D’Costa K, Harvey AR, Martins IJ, Hill F, Levy E, Shaw JE, Martins
RN (2010) Novel phage peptides attenuate beta amyloid42 catalysed hydrogen peroxide production and associated
neurotoxicity. Neurobiol Aging 31, 203-214.
Hock FJ, Gerhards HJ, Wiemer G, Usinger P, Geiger R
(1988) Learning and memory processes of an ACTH4-9
[906]
[907]
[908]
[909]
[910]
[911]
[912]
[913]
[914]
[915]
[916]
[917]
[918]
[919]
85
analog (ebiratide; Hoe 427) in mice and rats. Peptides 9,
575-581.
Wiemer G, Gerhards HJ, Hock FJ, Usinger P, Von RW,
Geiger R (1988) Neurochemical effects of the synthetic
ACTH4-9-analog Hoe 427 (Ebiratide) in rat brain. Peptides 9, 1081-1087.
Siegfried KR (1991) First clinical impressions with an
ACTH analog (HOE 427) in the treatment of Alzheimer’s
disease. Ann N Y Acad Sci 640, 280-283.
Manso Y, Adlard PA, Carrasco J, Vasak M, Hidalgo J
(2011) Metallothionein and brain inflammation. J Biol
Inorg Chem 16, 1103-1113.
Manso Y, Carrasco J, Comes G, Meloni G, Adlard PA,
Bush AI, Vasak M, Hidalgo J (2012) Characterization
of the role of metallothionein-3 in an animal model of
Alzheimer’s disease. Cell Mol Life Sci 69, 3683-3700.
Pelsman A, Hoyo-Vadillo C, Gudasheva TA, Seredenin
SB, Ostrovskaya RU, Busciglio J (2003) GVS-111 prevents oxidative damage and apoptosis in normal and
Down’s syndrome human cortical neurons. Int J Dev Neurosci 21, 117-124.
Ostrovskaya RU, Romanova GA, Barskov IV, Shanina
EV, Gudasheva TA, Victorov IV, Voronina TA, Seredenin SB (1999) Memory restoring and neuroprotective
effects of the proline-containing dipeptide, GVS-111, in a
photochemical stroke model. Behav Pharmacol 10, 549553.
Ostrovskaya RU, Mirsoev TK, Romanova GA, Gudasheva
TA, Kravchenko EV, Trofimov CC, Voronina TA, Seredenin SB (2001) Proline-containing dipeptide GVS-111
retains nootropic activity after oral administration. Bull
Exp Biol Med 132, 959-962.
Ostrovskaya RU, Gruden MA, Bobkova NA, Sewell RD,
Gudasheva TA, Samokhin AN, Seredinin SB, Noppe W,
Sherstnev VV, Morozova-Roche LA (2007) The nootropic
and neuroprotective proline-containing dipeptide noopept
restores spatial memory and increases immunoreactivity to
amyloid in an Alzheimer’s disease model. J Psychopharmacol 21, 611-619.
Ostrovskaya RU, Belnik AP, Storozheva ZI (2008)
Noopept efficiency in experimental Alzheimer disease
(cognitive deficiency caused by beta-amyloid25-35 injection into Meynert basal nuclei of rats). Bull Exp Biol Med
146, 77-80.
Ostrovskaya RU, Gudasheva TA, Zaplina AP, Vahitova JV,
Salimgareeva MH, Jamidanov RS, Seredenin SB (2008)
Noopept stimulates the expression of NGF and BDNF in
rat hippocampus. Bull Exp Biol Med 146, 334-337.
Kovalenko LP, Shipaeva EV, Alekseeva SV, Pronin AV,
Durnev AD, Gudasheva TA, Ostrovskaja RU, Seredenin
SB (2007) Immunopharmacological properties of noopept.
Bull Exp Biol Med 144, 49-52.
Neznamov GG, Teleshova ES (2009) Comparative studies of Noopept and piracetam in the treatment of patients
with mild cognitive disorders in organic brain diseases of
vascular and traumatic origin. Neurosci Behav Physiol 39,
311-321.
Kondratenko RV, Derevyagin VI, Skrebitsky VG (2010)
Novel nootropic dipeptide Noopept increases inhibitory
synaptic transmission in CA1 pyramidal cells. Neurosci
Lett 476, 70-73.
Vorobyov V, Kaptsov V, Kovalev G, Sengpiel F (2011)
Effects of nootropics on the EEG in conscious rats and
their modification by glutamatergic inhibitors. Brain Res
Bull 85, 123-132.
86
[920]
[921]
[922]
[923]
[924]
[925]
[926]
[927]
[928]
[929]
[930]
[931]
[932]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Jia X, Gharibyan AL, Ohman A, Liu Y, Olofsson
A, Morozova-Roche LA (2011) Neuroprotective and
nootropic drug noopept rescues alpha-synuclein amyloid
cytotoxicity. J Mol Biol 414, 699-712.
Hirano M, Hirate K, Miyake N (1998) NC-1900, a
[pGlu4,Cyt6]AVP(4-9) analogue, facilitates the learning
performance of rats on delayed nonmatching to sample
task in Y-water maze. Methods Find Exp Clin Pharmacol
20, 567-573.
Tanaka T, Yamada K, Senzaki K, Narimatsu H, Nishimura
K, Kameyama T, Nabeshima T (1998) NC-1900, an active
fragment analog of arginine vasopressin, improves learning and memory deficits induced by beta-amyloid protein
in rats. Eur J Pharmacol 352, 135-142.
Hori E, Uwano T, Tamura R, Miyake N, Nishijo H, Ono T
(2002) Effects of a novel arginine-vasopressin derivative,
NC-1900, on the spatial memory impairment of rats with
transient forebrain ischemia. Brain Res Cogn Brain Res
13, 1-15.
Ishida T, Sato T, Irifune M, Tanaka K, Hirate K, Nakamura
N, Nishikawa T (2007) Inhibitory effect of cyclooxygenase inhibitors on the step-through passive avoidance
performance in mice treated with NC-1900, an argininevasopressin fragment analog. Methods Find Exp Clin
Pharmacol 29, 315-320.
Sato T, Ishida T, Irifune M, Tanaka K, Hirate K, Nakamura N, Nishikawa T (2007) Effect of NC-1900, an active
fragment analog of arginine vasopressin, and inhibitors of
arachidonic acid metabolism on performance of a passive
avoidance task in mice. Eur J Pharmacol 560, 36-41.
Fotinopoulou A, Tsachaki M, Vlavaki M, Poulopoulos
A, Rostagno A, Frangione B, Ghiso J, Efthimiopoulos
S (2005) BRI2 interacts with amyloid precursor protein
(APP) and regulates amyloid beta (Abeta) production.
J Biol Chem 280, 30768-30772.
Peng S, Fitzen M, Jornvall H, Johansson J (2010) The
extracellular domain of Bri2 (ITM2B) binds the ABri
peptide (1-23) and amyloid beta-peptide (Abeta1-40):
Implications for Bri2 effects on processing of amyloid precursor protein and Abeta aggregation. Biochem Biophys
Res Commun 393, 356-361.
Matsuda S, Giliberto L, Matsuda Y, Davies P, McGowan E,
Pickford F, Ghiso J, Frangione B, D’Adamio L (2005) The
familial dementia BRI2 gene binds the Alzheimer gene
amyloid-beta precursor protein and inhibits amyloid-beta
production. J Biol Chem 280, 28912-28916.
Matsuda S, Giliberto L, Matsuda Y, McGowan EM,
D’Adamio L (2008) BRI2 inhibits amyloid beta-peptide
precursor protein processing by interfering with the
docking of secretases to the substrate. J Neurosci 28, 86688676.
Matsuda S, Matsuda Y, Snapp EL, D’Adamio L
(2011) Maturation of BRI2 generates a specific inhibitor
that reduces APP processing at the plasma membrane
and in endocytic vesicles. Neurobiol Aging 32, 14001408.
Kim J, Miller VM, Levites Y, West KJ, Zwizinski CW,
Moore BD, Troendle FJ, Bann M, Verbeeck C, Price RW,
Smithson L, Sonoda L, Wagg K, Rangachari V, Zou F,
Younkin SG, Graff-Radford N, Dickson D, Rosenberry T,
Golde TE (2008) BRI2 (ITM2b) inhibits Abeta deposition
in vivo. J Neurosci 28, 6030-6036.
Tsachaki M, Ghiso J, Efthimiopoulos S (2008) BRI2 as a
central protein involved in neurodegeneration. Biotechnol
J 3, 1548-1554.
[933]
[934]
[935]
[936]
[937]
[938]
[939]
[940]
[941]
[942]
[943]
[944]
[945]
[946]
[947]
Tsachaki M, Serlidaki D, Fetani A, Zarkou V, Rozani I,
Ghiso J, Efthimiopoulos S (2011) Glycosylation of BRI2
on asparagine 170 is involved in its trafficking to the cell
surface but not in its processing by furin or ADAM10.
Glycobiology 21, 1382-1388.
Findeis MA (2007) The role of amyloid beta peptide 42 in
Alzheimer’s disease. Pharmacol Ther 116, 266-286.
Gunstad J, Spitznagel MB, Glickman E, Alexander T,
Juvancic-Heltzel J, Walter K, Murray L (2008) betaAmyloid is associated with reduced cognitive function in
healthy older adults. J Neuropsychiatry Clin Neurosci 20,
327-330.
Cosentino SA, Stern Y, Sokolov E, Scarmeas N, Manly
JJ, Tang MX, Schupf N, Mayeux RP (2010) Plasma
beta-amyloid and cognitive decline. Arch Neurol 67, 14851490.
Parihar MS, Brewer GJ (2010) Amyloid-beta as a modulator of synaptic plasticity. J Alzheimers Dis 22, 741-763.
Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ,
Grodstein F (2012) Plasma amyloid-beta as a predictor of
dementia and cognitive decline: A systematic review and
meta-analysis. Arch Neurol 69, 824-831.
Koivunen J, Karrasch M, Scheinin NM, Aalto S, Vahlberg
T, Nagren K, Helin S, Viitanen M, Rinne JO (2012) Cognitive decline and amyloid accumulation in patients with
mild cognitive impairment. Dement Geriatr Cogn Disord
34, 31-37.
Chetelat G, Villemagne VL, Bourgeat P, Pike KE, Jones
G, Ames D, Ellis KA, Szoeke C, Martins RN, O’Keefe
GJ, Salvado O, Masters CL, Rowe CC (2010) Relationship between atrophy and beta-amyloid deposition in
Alzheimer disease. Ann Neurol 67, 317-324.
Chetelat G, Villemagne VL, Villain N, Jones G, Ellis
KA, Ames D, Martins RN, Masters CL, Rowe CC (2012)
Accelerated cortical atrophy in cognitively normal elderly
with high beta-amyloid deposition. Neurology 78, 477484.
Chetelat G, Villemagne VL, Pike KE, Ellis KA, Ames
D, Masters CL, Rowe CC (2012) Relationship between
memory performance and beta-amyloid deposition at different stages of Alzheimer’s disease. Neurodegener Dis
10, 141-144.
Klyubin I, Cullen WK, Hu NW, Rowan MJ (2012)
Alzheimer’s disease Abeta assemblies mediating rapid disruption of synaptic plasticity and memory. Mol Brain 5,
25.
Cavallucci V, D’Amelio M, Cecconi F (2012) Abeta toxicity in Alzheimer’s disease. Mol Neurobiol 45, 366-378.
Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid betaprotein: Synaptic and network dysfunction. Cold Spring
Harb Perspect Med 2, a006338.
Reitz C (2012) Alzheimer’s disease and the amyloid cascade hypothesis: A critical review. Int J Alzheimers Dis
2012, 369808.
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H,
Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del TK, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette
CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA,
Kovari E, Kukull WA, Leverenz JB, Love S, Mackenzie
IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski
JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG
(2012) Correlation of Alzheimer disease neuropathologic
changes with cognitive status: A review of the literature. J
Neuropathol Exp Neurol 71, 362-381.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[948]
[949]
[950]
[951]
[952]
[953]
[954]
[955]
[956]
[957]
[958]
[959]
[960]
[961]
[962]
[963]
[964]
[965]
[966]
[967]
[968]
[969]
Kline A (2012) Apolipoprotein E, amyloid-beta clearance and therapeutic opportunities in Alzheimer’s disease.
Alzheimers Res Ther 4, 32.
Soto C, Kindy MS, Baumann M, Frangione B (1996) Inhibition of Alzheimer’s amyloidosis by peptides that prevent
beta-sheet conformation. Biochem Biophys Res Commun
226, 672-680.
Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castano EM, Frangione B (1998) Beta-sheet breaker peptides
inhibit fibrillogenesis in a rat brain model of amyloidosis: Implications for Alzheimer’s therapy. Nat Med 4, 822826.
Zagorski MG (1998) Amyloid aggregation inhibitors.
IDrugs 1, 17-18.
Findeis MA (1999) ␤-Amyloid aggregation inhibitors.
Current Opin CNS Invest Druigs 1, 333-339.
Findeis MA, Musso GM, rico-Muendel CC, Benjamin
HW, Hundal AM, Lee JJ, Chin J, Kelley M, Wakefield
J, Hayward NJ, Molineaux SM (1999) Modified-peptide
inhibitors of amyloid beta-peptide polymerization. Biochemistry 38, 6791-6800.
Soto C (1999) Plaque busters: Strategies to inhibit amyloid
formation in Alzheimer’s disease. Mol Med Today 5, 343350.
Soto C (1999) b-Amyloid disrupting drugs. CNS Drugs
12, 347-356.
Moore CI, Wolfe MS (1999) Inhibition of ␤-amyloid formation as a therapeutic strategy. Exp Opin Ther Patents 9,
135-146.
Findeis MA, Lee JJ, Kelley M, Wakefield JD, Zhang MH,
Chin J, Kubasek W, Molineaux SM (2001) Characterization of cholyl-leu-val-phe-phe-ala-OH as an inhibitor of
amyloid beta-peptide polymerization. Amyloid 8, 231-241.
Adessi C, Soto C (2002) Beta-sheet breaker strategy for
the treatment of Alzheimer’s disease. Drug Dev Res 56,
184-193.
Findeis MA (2002) Peptide inhibitors of beta amyloid
aggregation. Curr Top Med Chem 2, 417-423.
Levine H (2002) The challenge of inhibiting Abeta polymerization. Curr Med Chem 9, 1121-1133.
Levine H III (2005) Multiple ligand binding sites on A
beta(1-40) fibrils. Amyloid 12, 5-14.
Soto C, Estrada L (2005) Amyloid inhibitors and betasheet breakers. Subcell Biochem 38, 351-364.
Lansbury PT, Lashuel HA (2006) A century-old debate
on protein aggregation and neurodegeneration enters the
clinic. Nature 443, 774-779.
Levine H III (2007) Small molecule inhibitors of Abeta
assembly. Amyloid 14, 185-197.
Stains CI, Mondal K, Ghosh I (2007) Molecules that target
beta-amyloid. ChemMedChem 2, 1674-1692.
Hawkes CA, Ng V, McLaurin J (2009) Small molecule
inhibitors of A␤-aggregation and neurotoxicity. Drug Dev
Res 70, 111-124.
Haydar SN, Yun H, Staal RGW, Hirst WD (2009)
Small-molecule protein-protein interaction inhibitors as
therapeutic agents for neurodegenerative diseases: Recent
progress and future directions. Ann Rep Med Chem 44,
51-69.
Yadav A, Sonker M (2009) Perspectives in designing anti
aggregation agents as Alzheimer disease drugs. Eur J Med
Chem 44, 3866-3873.
Kim HY, Kim Y, Han G, Kim DJ (2010) Regulation of in
vitro Abeta1-40 aggregation mediated by small molecules.
J Alzheimers Dis 22, 73-85.
[970]
[971]
[972]
[973]
[974]
[975]
[976]
[977]
[978]
[979]
[980]
[981]
[982]
[983]
[984]
[985]
87
Butterfield SM, Lashuel HA (2010) Amyloidogenic
protein-membrane interactions: Mechanistic insight from
model systems. Angew Chem Int Ed Engl 49, 56285654.
Scherzer-Attali R, Pellarin R, Convertino M, FrydmanMarom A, Egoz-Matia N, Peled S, Levy-Sakin M, Shalev
DE, Caflisch A, Gazit E, Segal D (2010) Complete phenotypic recovery of an Alzheimer’s disease model by a
quinone-tryptophan hybrid aggregation inhibitor. PLoS
One 5, e11101.
Dorgeret B, Khemtemourian L, Correia I, Soulier JL,
Lequin O, Ongeri S (2011) Sugar-based peptidomimetics inhibit amyloid beta-peptide aggregation. Eur J Med
Chem 46, 5959-5969.
Richman M, Wilk S, Skirtenko N, Perelman A,
Rahimipour S (2011) Surface-modified protein microspheres capture amyloid-beta and inhibit its aggregation
and toxicity. Chemistry 17, 11171-11177.
Butterfield S, Hejjaoui M, Fauvet B, Awad L, Lashuel HA
(2012) Chemical strategies for controlling protein folding and elucidating the molecular mechanisms of amyloid
formation and toxicity. J Mol Biol 421, 204-236.
Scherzer-Attali R, Shaltiel-Karyo R, Adalist YH, Segal
D, Gazit E (2012) Generic inhibition of amyloidogenic proteins by two naphthoquinone-tryptophan hybrid
molecules. Proteins 80, 1962-1973.
Scherzer-Attali R, Farfara D, Cooper I, Levin A, BenRomano T, Trudler D, Vientrov M, Shaltiel-Karyo R,
Shalev DE, Segev-Amzaleg N, Gazit E, Segal D, Frenkel
D (2012) Naphthoquinone-tyrptophan reduces neurotoxic
Abeta*56 levels and improves cognition in Alzheimer’s
disease animal model. Neurobiol Dis 46, 663-672.
Ratner M (2009) Spotlight focuses on protein-misfolding
therapies. Nat Biotechnol 27, 874.
Plante-Bordeneuve V, Said G (2011) Familial amyloid
polyneuropathy. Lancet Neurol 10, 1086-1097.
Yamamoto T, Muto K, Komiyama M, Canivet J, Yamaguchi J, Itami K (2011) Nickel-catalyzed C-H arylation
of azoles with haloarenes: Scope, mechanism, and applications to the synthesis of bioactive molecules. Chemistry
17, 10113-10122.
Bulawa CE, Connelly S, Devit M, Wang L, Weigel
C, Fleming JA, Packman J, Powers ET, Wiseman RL,
Foss TR, Wilson IA, Kelly JW, Labaudiniere R (2012)
Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad
Sci U S A 109, 9629-9634.
Du J, Cho PY, Yang DT, Murphy RM (2012) Identification of beta-amyloid-binding sites on transthyretin. Protein
Eng Des Sel 25, 337-345.
Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW
(2012) The transthyretin amyloidoses: From delineating
the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol 421,
185-203.
Buxbaum JN, Linke RP (2012) A molecular history of the
amyloidoses. J Mol Biol 421, 142-159.
Dember LM, Hawkins PN, Hazenberg BP, Gorevic PD,
Merlini G, Butrimiene I, Livneh A, Lesnyak O, Puechal
X, Lachmann HJ, Obici L, Balshaw R, Garceau D, Hauck
W, Skinner M (2007) Eprodisate for the treatment of renal
disease in AA amyloidosis. N Engl J Med 356, 23492360.
Manenti L, Tansinda P, Vaglio A (2007) Eprodisate in AA
amyloidosis. N Engl J Med 357, 1153-1154.
88
[986]
[987]
[988]
[989]
[990]
[991]
[992]
[993]
[994]
[995]
[996]
[997]
[998]
[999]
[1000]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Manenti L, Tansinda P, Vaglio A (2008) Eprodisate in amyloid A amyloidosis: A novel therapeutic approach? Expert
Opin Pharmacother 9, 2175-2180.
Rule AD, Leung N (2007) Eprodisate slows the progression of renal disease in patients with AA amyloidosis. Nat
Clin Pract Nephrol 3, 592-593.
Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith
CH, Mahony J, Smith S, Borrie M, Decoteau E, Davidson
W, McDougall A, Gnarpe J, O’DONNell M, Chernesky
M (2004) A randomized, controlled trial of doxycycline
and rifampin for patients with Alzheimer’s disease. J Am
Geriatr Soc 52, 381-387.
Salloway S, Sperling R, Keren R, Porsteinsson AP, van
Dyck CH, Tariot PN, Gilman S, Arnold D, Abushakra S,
Hernandez C, Crans G, Liang E, Quinn G, Bairu M, Pastrak
A, Cedarbaum JM (2011) A phase 2 randomized trial of
ELND005, scyllo-inositol, in mild to moderate Alzheimer
disease. Neurology 77, 1253-1262.
McLaurin J, Golomb R, Jurewicz A, Antel JP, Fraser
PE (2000) Inositol stereoisomers stabilize an oligomeric
aggregate of Alzheimer amyloid beta peptide and inhibit
abeta -induced toxicity. J Biol Chem 275, 18495-18502.
McLaurin J, Kierstead ME, Brown ME, Hawkes CA,
Lambermon MH, Phinney AL, Darabie AA, Cousins JE,
French JE, Lan MF, Chen F, Wong SS, Mount HT, Fraser
PE, Westaway D, St George-Hyslop P (2006) Cyclohexanehexol inhibitors of Abeta aggregation prevent and
reverse Alzheimer phenotype in a mouse model. Nat Med
12, 801-808.
Fenili D, Brown M, Rappaport R, McLaurin J (2007)
Properties of scyllo-inositol as a therapeutic treatment of
AD-like pathology. J Mol Med (Berl) 85, 603-611.
Hawkes CA, Deng LH, Shaw JE, Nitz M, McLaurin J
(2010) Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and
pathology in a mouse model of Alzheimer’s disease. Eur
J Neurosci 31, 203-213.
Townsend M, Cleary JP, Mehta T, Hofmeister J, Lesne S,
O’Hare E, Walsh DM, Selkoe DJ (2006) Orally available
compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers. Ann Neurol 60, 668-676.
Griffith HR, Den Hollander JA, Stewart CC, Evanochko
WT, Buchthal SD, Harrell LE, Zamrini EY, Brockington JC, Marson DC (2007) Elevated brain scyllo-inositol
concentrations in patients with Alzheimer’s disease. NMR
Biomed 20, 709-716.
Sun Y, Zhang G, Hawkes CA, Shaw JE, McLaurin J, Nitz
M (2008) Synthesis of scyllo-inositol derivatives and their
effects on amyloid beta peptide aggregation. Bioorg Med
Chem 16, 7177-7184.
Vasdev N, Chio J, van Oosten EM, Nitz M, McLaurin
J, Vines DC, Houle S, Reilly RM, Wilson AA (2009)
Synthesis and preliminary biological evaluations of [18F]1-deoxy-1-fluoro-scyllo-inositol. Chem Commun (Camb)
5527-5529.
Sinha S, Du Z, Maiti P, Klarner FG, Schrader T, Wang C,
Bitan G (2012) Comparison of Three Amyloid Assembly
Inhibitors: The Sugar scyllo-Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01.
ACS Chem Neurosci 3, 451-458.
Gunther EC, Strittmatter SM (2010) Beta-amyloid
oligomers and cellular prion protein in Alzheimer’s disease. J Mol Med (Berl) 88, 331-338.
Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment
[1001]
[1002]
[1003]
[1004]
[1005]
[1006]
[1007]
[1008]
[1009]
[1010]
[1011]
[1012]
[1013]
[1014]
of synaptic plasticity by amyloid-beta oligomers. Nature
457, 1128-1132.
Nygaard HB, Strittmatter SM (2009) Cellular prion protein
mediates the toxicity of beta-amyloid oligomers: Implications for Alzheimer disease. Arch Neurol 66, 13251328.
Chung E, Ji Y, Sun Y, Kascsak RJ, Kascsak RB, Mehta PD,
Strittmatter SM, Wisniewski T (2010) Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive
deficits in an Alzheimer’s disease model mouse. BMC
Neurosci 11, 130.
Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Lauren
J, Gimbel ZA, Strittmatter SM (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion
protein. J Neurosci 30, 6367-6374.
Kroth H, Ansaloni A, Varisco Y, Jan A, Sreenivasachary
N, Rezaei-Ghaleh N, Giriens V, Lohmann S, Lopez-Deber
MP, Adolfsson O, Pihlgren M, Paganetti P, Froestl W,
Nagel-Steger L, Willbold D, Schrader T, Zweckstetter M,
Pfeifer A, Lashuel HA, Muhs A (2012) Discovery and
structure activity relationship of small molecule inhibitors
of toxic beta-amyloid-42 fibril formation. J Biol Chem 287,
34786-34800.
Rzepecki P, Wehner M, Molt O, Zadmard R, Harms K,
Schrader T (2003) Aminopyrazole oligomers for betasheet stabilization of peptides. Synthesis, 1815-1826.
Rzepecki P, Nagel-Steger L, Feuerstein S, Linne U, Molt
O, Zadmard R, Aschermann K, Wehner M, Schrader T,
Riesner D (2004) Prevention of Alzheimer’s diseaseassociated Abeta aggregation by rationally designed
nonpeptidic beta-sheet ligands. J Biol Chem 279, 4749747505.
Nagel-Steger L, Demeler B, Meyer-Zaika W, Hochdorffer
K, Schrader T, Willbold D (2010) Modulation of aggregate
size- and shape-distributions of the amyloid-beta peptide
by a designed beta-sheet breaker. Eur Biophys J 39, 415422.
Rzepecki P, Hochdorffer K, Schaller T, Zienau J, Harms
K, Ochsenfeld C, Xie X, Schrader T (2008) Hierarchical
self-assembly of aminopyrazole peptides into nanorosettes
in water. J Am Chem Soc 130, 586-591.
Hochdorffer K, Marz-Berberich J, Nagel-Steger L, Epple
M, Meyer-Zaika W, Horn AH, Sticht H, Sinha S, Bitan G,
Schrader T (2011) Rational design of beta-sheet ligands
against Abeta42-induced toxicity. J Am Chem Soc 133,
4348-4358.
Rzepecki P, Geib N, Peifer M, Biesemeier F, Schrader T
(2007) Synthesis and binding studies of Alzheimer ligands
on solid support. J Org Chem 72, 3614-3624.
Cernovska K, Kemter M, Gallmeier HC, Rzepecki P,
Schrader T, Konig B (2004) PEG-supported synthesis of
pyrazole oligoamides with peptide beta-sheet affinity. Org
Biomol Chem 2, 1603-1611.
Rzepecki P, Schrader T (2005) beta-Sheet ligands in
action: KLVFF recognition by aminopyrazole hybrid
receptors in water. J Am Chem Soc 127, 3016-3025.
Fricke H, Gerlach A, Unterberg C, Wehner M, Schrader T,
Gerhards M (2009) Interactions of small protected peptides with aminopyrazole derivatives: The efficiency of
blocking a beta-sheet model in the gas phase. Angew Chem
Int Ed Engl 48, 900-904.
Lecanu L, Tillement L, Rammouz G, Tillement JP, Greeson J, Papadopoulos V (2009) Caprospinol: Moving from
a neuroactive steroid to a neurotropic drug. Expert Opin
Investig Drugs 18, 265-276.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1015]
[1016]
[1017]
[1018]
[1019]
[1020]
[1021]
[1022]
[1023]
[1024]
[1025]
[1026]
[1027]
[1028]
Lecanu L, Rammouz G, McCourty A, Sidahmed EK,
Greeson J, Papadopoulos V (2010) Caprospinol reduces
amyloid deposits and improves cognitive function in a rat
model of Alzheimer’s disease. Neuroscience 165, 427-435.
Tillement L, Lecanu L, Papadopoulos V (2011) Further
evidence on mitochondrial targeting of beta-amyloid and
specificity of beta-amyloid-induced mitotoxicity in neurons. Neurodegener Dis 8, 331-344.
Papadopoulos V, Lecanu L (2012) Caprospinol: Discovery
of a steroid drug candidate to treat Alzheimer’s disease
based on 22R-hydroxycholesterol structure and properties.
J Neuroendocrinol 24, 93-101.
Howlett DR, George AR, Owen DE, Ward RV, Markwell RE (1999) Common structural features determine
the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer beta-amyloid fibril
formation. Biochem J 343 Pt 2, 419-423.
Fokkens M, Schrader T, Klarner FG (2005) A molecular tweezer for lysine and arginine. J Am Chem Soc 127,
14415-14421.
Sinha S, Lopes DH, Du Z, Pang ES, Shanmugam A,
Lomakin A, Talbiersky P, Tennstaedt A, McDaniel K,
Bakshi R, Kuo PY, Ehrmann M, Benedek GB, Loo JA,
Klarner FG, Schrader T, Wang C, Bitan G (2011) Lysinespecific molecular tweezers are broad-spectrum inhibitors
of assembly and toxicity of amyloid proteins. J Am Chem
Soc 133, 16958-16969.
Prabhudesai S, Sinha S, Attar A, Kotagiri A, Fitzmaurice AG, Lakshmanan R, Ivanova MI, Loo JA, Klarner
FG, Schrader T, Stahl M, Bitan G, Bronstein JM (2012)
A novel “molecular tweezer” inhibitor of alpha-synuclein
neurotoxicity in vitro and in vivo. Neurotherapeutics 9,
464-476.
Klarner FG, Schrader T (2012) Aromatic interactions by
molecular tweezers and clips in chemical and biological
systems. Acc Chem Res, doi: 10.1021/ar300061c [Epub
ahead of print].
Talbiersky P, Bastkowski F, Klarner FG, Schrader T (2008)
Molecular clip and tweezer introduce new mechanisms of
enzyme inhibition. J Am Chem Soc 130, 9824-9828.
Klarner FG, Kahlert B, Nellesen A, Zienau J, Ochsenfeld C, Schrader T (2006) Molecular tweezer and clip
in aqueous solution: Unexpected self-assembly, powerful host-guest complex formation, quantum chemical 1H
NMR shift calculation. J Am Chem Soc 128, 4831-4841.
Echeverria V, Zeitlin R (2012) Cotinine: A potential new
therapeutic agent against Alzheimer’s disease. CNS Neurosci Ther 18, 517-523.
Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De LA, Vergani C, De Simoni MG
(2004) Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid
accumulation in a mouse model of Alzheimer’s disease.
J Neurosci 24, 4181-4186.
Timmer NM, Herbert MK, Kleinovink JW, Kiliaan AJ,
de Waal RM, Verbeek MM (2010) Limited expression
of heparan sulphate proteoglycans associated with Abeta
deposits in the APPswe/PS1dE9 mouse model for Alzheimer’s disease. Neuropathol Appl Neurobiol 36, 478-486.
Timmer NM, van DL, van der Zee CE, Kiliaan A, de
Waal RM, Verbeek MM (2010) Enoxaparin treatment
administered at both early and late stages of amyloid beta
deposition improves cognition of APPswe/PS1dE9 mice
with differential effects on brain Abeta levels. Neurobiol
Dis 40, 340-347.
[1029]
[1030]
[1031]
[1032]
[1033]
[1034]
[1035]
[1036]
[1037]
[1038]
[1039]
[1040]
[1041]
[1042]
[1043]
[1044]
89
Matharu B, Gibson G, Parsons R, Huckerby TN, Moore
SA, Cooper LJ, Millichamp R, Allsop D, Austen B (2009)
Galantamine inhibits beta-amyloid aggregation and cytotoxicity. J Neurol Sci 280, 49-58.
Petrlova J, Kalai T, Maezawa I, Altman R, Harishchandra
G, Hong HS, Bricarello DA, Parikh AN, Lorigan GA, Jin
LW, Hideg K, Voss JC (2012) The influence of spin-labeled
fluorene compounds on the assembly and toxicity of the
abeta Peptide. PLoS One 7, e35443.
Chavant F, Deguil J, Pain S, Ingrand I, Milin S, Fauconneau B, Perault-Pochat MC, Lafay-Chebassier C (2010)
Imipramine, in part through tumor necrosis factor alpha
inhibition, prevents cognitive decline and beta-amyloid
accumulation in a mouse model of Alzheimer’s disease.
J Pharmacol Exp Ther 332, 505-514.
Byun JH, Kim H, Kim Y, Mook-Jung I, Kim DJ, Lee
WK, Yoo KH (2008) Aminostyrylbenzofuran derivatives
as potent inhibitors for Abeta fibril formation. Bioorg Med
Chem Lett 18, 5591-5593.
Lee YS, Kim HY, Kim Y, Seo JH, Roh EJ, Han H,
Shin KJ (2012) Small molecules that protect against betaamyloid-induced cytotoxicity by inhibiting aggregation of
beta-amyloid. Bioorg Med Chem 20, 4921-4935.
Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS,
Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S,
Suh YH (2007) Minocycline attenuates neuronal cell death
and improves cognitive impairment in Alzheimer’s disease
models. Neuropsychopharmacology 32, 2393-2404.
Burgos-Ramos E, Puebla-Jimenez L, Rilla-Ferreiro E
(2008) Minocycline provides protection against betaamyloid(25-35)-induced alterations of the somatostatin
signaling pathway in the rat temporal cortex. Neuroscience
154, 1458-1466.
Burgos-Ramos E, Puebla-Jimenez L, Rilla-Ferreiro
E (2009) Minocycline prevents Abeta(25-35)-induced
reduction of somatostatin and neprilysin content in rat
temporal cortex. Life Sci 84, 205-210.
Seabrook TJ, Jiang L, Maier M, Lemere CA (2006)
Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53, 776-782.
Fan R, Xu F, Previti ML, Davis J, Grande AM, Robinson JK, Van Nostrand WE (2007) Minocycline reduces
microglial activation and improves behavioral deficits in
a transgenic model of cerebral microvascular amyloid.
J Neurosci 27, 3057-3063.
Parachikova A, Vasilevko V, Cribbs DH, LaFerla FM,
Green KN (2010) Reductions in amyloid-beta-derived
neuroinflammation, with minocycline, restore cognition
but do not significantly affect tau hyperphosphorylation.
J Alzheimers Dis 21, 527-542.
Kreutzmann P, Wolf G, Kupsch K (2010) Minocycline
recovers MTT-formazan exocytosis impaired by amyloid
beta peptide. Cell Mol Neurobiol 30, 979-984.
Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger
DP, Anderton BH (2009) Minocycline reduces the development of abnormal tau species in models of Alzheimer’s
disease. FASEB J 23, 739-750.
Noble W, Garwood CJ, Hanger DP (2009) Minocycline as
a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding. Prion 3, 78-83.
Garwood CJ, Cooper JD, Hanger DP, Noble W (2010)
Anti-inflammatory impact of minocycline in a mouse
model of tauopathy. Front Psychiatr 1, 136.
Song Y, Wei EQ, Zhang WP, Ge QF, Liu JR, Wang ML,
Huang XJ, Hu X, Chen Z (2006) Minocycline protects
90
[1045]
[1046]
[1047]
[1048]
[1049]
[1050]
[1051]
[1052]
[1053]
[1054]
[1055]
[1056]
[1057]
[1058]
[1059]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
PC12 cells against NMDA-induced injury via inhibiting
5-lipoxygenase activation. Brain Res 1085, 57-67.
Hashimoto K (2011) Can minocycline prevent the onset of
Alzheimer’s disease? Ann Neurol 69, 739-740.
Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, Dursun S, Dunn G, Deakin
B (2012) Minocycline benefits negative symptoms in
early schizophrenia: A randomised double-blind placebocontrolled clinical trial in patients on standard treatment.
J Psychopharmacol 26, 1185-1193.
Tomiyama T, Asano S, Suwa Y, Morita T, Kataoka K, Mori
H, Endo N (1994) Rifampicin prevents the aggregation and
neurotoxicity of amyloid beta protein in vitro. Biochem
Biophys Res Commun 204, 76-83.
Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S,
Kaneko H, Endo N (1996) Inhibition of amyloid beta
protein aggregation and neurotoxicity by rifampicin. Its
possible function as a hydroxyl radical scavenger. J Biol
Chem 271, 6839-6844.
Tomiyama T, Kaneko H, Kataoka K, Asano S, Endo N
(1997) Rifampicin inhibits the toxicity of pre-aggregated
amyloid peptides by binding to peptide fibrils and preventing amyloid-cell interaction. Biochem J 322(Pt 3),
859-865.
Qosa H, Abuznait AH, Hill RA, Kaddoumi A (2012)
Enhanced brain amyloid-beta clearance by rifampicin
and caffeine as a possible protective mechanism against
Alzheimer’s disease. J Alzheimers Dis 31, 151-165.
Forloni G, Colombo L, Girola L, Tagliavini F, Salmona
M (2001) Anti-amyloidogenic activity of tetracyclines:
Studies in vitro. FEBS Lett 487, 404-407.
Diomede L, Cassata G, Fiordaliso F, Salio M, Ami D,
Natalello A, Doglia SM, De LA, Salmona M (2010)
Tetracycline and its analogues protect Caenorhabditis elegans from beta amyloid-induced toxicity by targeting
oligomers. Neurobiol Dis 40, 424-431.
Averback P (1998) Spherons as a drug target in
Alzheimer’s disease. Drug News Perspect 11, 469-479.
Averback P, Morse D, Ghanbari H (1998) Bursting dense
microspheres (spherons) in Alzheimer’s disease: A review
of studies (1980–1997) on spherons and the pathogenesis
of Alzheimer’s disease. J Alzheimers Dis 1, 1-34.
Garofalo AW, Wone DW, Phuc A, Audia JE, Bales CA,
Dovey HF, Dressen DB, Folmer B, Goldbach EG, Guinn
AC, Latimer LH, Mabry TE, Nissen JS, Pleiss MA, Sohn S,
Thorsett ED, Tung JS, Wu J (2002) A series of C-terminal
amino alcohol dipeptide A beta inhibitors. Bioorg Med
Chem Lett 12, 3051-3053.
Friedman OM, Matsudaira P, Reis AH Jr, Simister N,
Correia I, Kew D, Wei JY, Pochapsky T (2007) Substituted
organosiloxanes as potential therapeutics for treatment and
prevention of neurodegenerative diseases. J Alzheimers
Dis 11, 291-300.
Wood SJ, MacKenzie L, Maleeff B, Hurle MR, Wetzel R
(1996) Selective inhibition of Abeta fibril formation. J Biol
Chem 271, 4086-4092.
Howlett DR, Perry AE, Godfrey F, Swatton JE, Jennings
KH, Spitzfaden C, Wadsworth H, Wood SJ, Markwell RE
(1999) Inhibition of fibril formation in beta-amyloid peptide by a novel series of benzofurans. Biochem J 340(Pt
1), 283-289.
Parker MH, Chen R, Conway KA, Lee DH, Luo C,
Boyd RE, Nortey SO, Ross TM, Scott MK, Reitz
AB (2002) Synthesis of (-)-5,8-dihydroxy-3R-methyl2R-(dipropylamino)-1,2,3,4-tetrahydronaphthale ne: An
[1060]
[1061]
[1062]
[1063]
[1064]
[1065]
[1066]
[1067]
[1068]
[1069]
[1070]
[1071]
[1072]
[1073]
[1074]
inhibitor of beta-amyloid(1-42) aggregation. Bioorg Med
Chem 10, 3565-3569.
Simons LJ, Caprathe BW, Callahan M, Graham JM,
Kimura T, Lai Y, LeVine H III, Lipinski W, Sakkab AT,
Tasaki Y, Walker LC, Yasunaga T, Ye Y, Zhuang N,
ugelli-Szafran CE (2009) The synthesis and structureactivity relationship of substituted N-phenyl anthranilic
acid analogs as amyloid aggregation inhibitors. Bioorg
Med Chem Lett 19, 654-657.
Merlini G, Ascari E, Amboldi N, Bellotti V, Arbustini E,
Perfetti V, Ferrari M, Zorzoli I, Marinone MG, Garini
P, et al. (1995) Interaction of the anthracycline 4 -iodo4 -deoxydoxorubicin with amyloid fibrils: Inhibition of
amyloidogenesis. Proc Natl Acad Sci U S A 92, 2959-2963.
Higaki JN, Chakravarty S, Bryant CM, Cowart LR, Harden
P, Scardina JM, Mavunkel B, Luedtke GR, Cordell B
(1999) A combinatorial approach to the identification of
dipeptide aldehyde inhibitors of beta-amyloid production.
J Med Chem 42, 3889-3898.
Kisilevsky R, Lemieux LJ, Fraser PE, Kong X, Hultin PG,
Szarek WA (1995) Arresting amyloidosis in vivo using
small-molecule anionic sulphonates or sulphates: Implications for Alzheimer’s disease. Nat Med 1, 143-148.
Kisilevsky R (1996) Anti-amyloid drugs: Potential in the
treatment of diseases associated with aging. Drugs Aging
8, 75-83.
Kisilevsky R (1997) Can deposition of amyloid be prevented in Alzheimer’s disease? Ann N Y Acad Sci 826,
117-127.
Tjernberg LO, Lilliehook C, Callaway DJ, Naslund J,
Hahne S, Thyberg J, Terenius L, Nordstedt C (1997)
Controlling amyloid beta-peptide fibril formation with
protease-stable ligands. J Biol Chem 272, 12601-12605.
Banks WA, Farr SA, Butt W, Kumar VB, Franko MW, Morley JE (2001) Delivery across the blood-brain barrier of
antisense directed against amyloid beta: Reversal of learning and memory deficits in mice overexpressing amyloid
precursor protein. J Pharmacol Exp Ther 297, 1113-1121.
Heal JR, Roberts GW, Christie G, Miller AD (2002) Inhibition of beta-amyloid aggregation and neurotoxicity by
complementary (antisense) peptides. Chembiochem 3, 8692.
Gestwicki JE, Crabtree GR, Graef IA (2004) Harnessing chaperones to generate small-molecule inhibitors of
amyloid beta aggregation. Science 306, 865-869.
Lin SJ, Shiao YJ, Chi CW, Yang LM (2004) Abeta aggregation inhibitors. Part 1: Synthesis and biological activity of
phenylazo benzenesulfonamides. Bioorg Med Chem Lett
14, 1173-1176.
Bose M, Gestwicki JE, Devasthali V, Crabtree GR, Graef
IA (2005) ‘Nature-inspired’ drug-protein complexes as
inhibitors of Abeta aggregation. Biochem Soc Trans 33,
543-547.
Lee KH, Shin BH, Shin KJ, Kim DJ, Yu J (2005) A hybrid
molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42). Biochem
Biophys Res Commun 328, 816-823.
Schwarzman AL, Tsiper M, Gregori L, Goldgaber D,
Frakowiak J, Mazur-Kolecka B, Taraskina A, Pchelina
S, Vitek MP (2005) Selection of peptides binding to the
amyloid ␤-protein reveals potential inhibitors of amyloid
formation. Amyloid 12, 199-209.
Cohen T, Frydman-Marom A, Rechter M, Gazit E (2006)
Inhibition of amyloid fibril formation and cytotoxicity by
hydroxyindole derivatives. Biochemistry 45, 4727-4735.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1075]
[1076]
[1077]
[1078]
[1079]
[1080]
[1081]
[1082]
[1083]
[1084]
[1085]
[1086]
[1087]
[1088]
[1089]
[1090]
[1091]
Dolphin GT, Dumy P, Garcia J (2006) Control of amyloid
beta-peptide protofibril formation by a designed template
assembly. Angew Chem Int Ed Engl 45, 2699-2702.
Etienne MA, Aucoin JP, Fu Y, McCarley RL, Hammer
RP (2006) Stoichiometric inhibition of amyloid betaprotein aggregation with peptides containing alternating
alpha,alpha-disubstituted amino acids. J Am Chem Soc
128, 3522-3523.
Inbar P, Yang J (2006) Inhibiting protein-amyloid interactions with small molecules: A surface chemistry approach.
Bioorg Med Chem Lett 16, 1076-1079.
Inbar P, Li CQ, Takayama SA, Bautista MR, Yang J
(2006) Oligo(ethylene glycol) derivatives of thioflavin T as
inhibitors of protein-amyloid interactions. Chembiochem
7, 1563-1566.
Kwak JW, Kim HK, Chae CB (2006) Potential lead for
an Alzheimer drug: A peptide that blocks intermolecular
interaction and amyloid beta protein-induced cytotoxicity.
J Med Chem 49, 4813-4817.
Orner BP, Liu L, Murphy RM, Kiessling LL (2006) Phage
display affords peptides that modulate beta-amyloid aggregation. J Am Chem Soc 128, 11882-11889.
Pai AS, Rubinstein I, Onyuksel H (2006) PEGylated phospholipid nanomicelles interact with beta-amyloid(1-42)
and mitigate its beta-sheet formation, aggregation and neurotoxicity in vitro. Peptides 27, 2858-2866.
Porat Y, Abramowitz A, Gazit E (2006) Inhibition of amyloid fibril formation by polyphenols: Structural similarity
and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 67, 27-37.
Byeon SR, Lee JH, Sohn JH, Kim DC, Shin KJ, Yoo KH,
Mook-Jung I, Lee WK, Kim DJ (2007) Bis-styrylpyridine
and bis-styrylbenzene derivatives as inhibitors for Abeta
fibril formation. Bioorg Med Chem Lett 17, 1466-1470.
Byeon SR, Jin YJ, Lim SJ, Lee JH, Yoo KH, Shin KJ, Oh
SJ, Kim DJ (2007) Ferulic acid and benzothiazole dimer
derivatives with high binding affinity to beta-amyloid fibrils. Bioorg Med Chem Lett 17, 4022-4025.
Dolphin GT, Ouberai M, Dumy P, Garcia J (2007)
Designed amyloid beta peptide fibril –a tool for highthroughput screening of fibril inhibitors. ChemMedChem
2, 1613-1623.
Chafekar SM, Malda H, Merkx M, Meijer EW, Viertl D,
Lashuel HA, Baas F, Scheper W (2007) Branched KLVFF
tetramers strongly potentiate inhibition of beta-amyloid
aggregation. Chembiochem 8, 1857-1864.
Etienne MA, Edwin NJ, Aucoin JP, Russo PS, McCarley
RL, Hammer RP (2007) Beta-amyloid protein aggregation. Methods Mol Biol 386, 203-225.
Flaherty DP, Walsh SM, Kiyota T, Dong Y, Ikezu T,
Vennerstrom JL (2007) Polyfluorinated bis-styrylbenzene
beta-amyloid plaque binding ligands. J Med Chem 50,
4986-4992.
Honson NS, Johnson RL, Huang W, Inglese J, Austin
CP, Kuret J (2007) Differentiating Alzheimer diseaseassociated aggregates with small molecules. Neurobiol Dis
28, 251-260.
Necula M, Kayed R, Milton S, Glabe CG (2007) Small
molecule inhibitors of aggregation indicate that amyloid
beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 282, 10311-10324.
Okuno H, Mori K, Okada T, Yokoyama Y, Suzuki H (2007)
Development of aggregation inhibitors for amyloid-beta
peptides and their evaluation by quartz-crystal microbalance. Chem Biol Drug Des 69, 356-361.
[1092]
[1093]
[1094]
[1095]
[1096]
[1097]
[1098]
[1099]
[1100]
[1101]
[1102]
[1103]
[1104]
[1105]
[1106]
91
Riviere C, Richard T, Quentin L, Krisa S, Merillon
JM, Monti JP (2007) Inhibitory activity of stilbenes on
Alzheimer’s beta-amyloid fibrils in vitro. Bioorg Med
Chem 15, 1160-1167.
Sato J, Takahashi T, Oshima H, Matsumura S, Mihara H
(2007) Design of peptides that form amyloid-like fibrils
capturing amyloid beta1-42 peptides. Chemistry 13, 77457752.
Takahashi T, Ohta K, Mihara H (2007) Embedding the
amyloid beta-peptide sequence in green fluorescent protein
inhibits Abeta oligomerization. Chembiochem 8, 985-988.
Austen BM, Paleologou KE, Ali SA, Qureshi MM, Allsop
D, El-Agnaf OM (2008) Designing peptide inhibitors for
oligomerization and toxicity of Alzheimer’s beta-amyloid
peptide. Biochemistry 47, 1984-1992.
Bravo R, Arimon M, Valle-Delgado JJ, Garcia R, Durany
N, Castel S, Cruz M, Ventura S, Fernandez-Busquets X
(2008) Sulfated polysaccharides promote the assembly of
amyloid beta(1-42) peptide into stable fibrils of reduced
cytotoxicity. J Biol Chem 283, 32471-32483.
Cabaleiro-Lago C, Quinlan-Pluck F, Lynch I, Lindman S,
Minogue AM, Thulin E, Walsh DM, Dawson KA, Linse S
(2008) Inhibition of amyloid beta protein fibrillation by
polymeric nanoparticles. J Am Chem Soc 130, 1543715443.
Cellamare S, Stefanachi A, Stolfa DA, Basile T, Catto
M, Campagna F, Sotelo E, Acquafredda P, Carotti A
(2008) Design, synthesis, and biological evaluation of
glycine-based molecular tongs as inhibitors of Abeta1-40
aggregation in vitro. Bioorg Med Chem 16, 4810-4822.
Dolphin GT, Chierici S, Ouberai M, Dumy P, Garcia J
(2008) A multimeric quinacrine conjugate as a potential inhibitor of Alzheimer’s beta-amyloid fibril formation.
Chembiochem 9, 952-963.
Esteras-Chopo A, Pastor MT, Serrano L, Lopez de la
PM (2008) New strategy for the generation of specific
D-peptide amyloid inhibitors. J Mol Biol 377, 1372-1381.
Feng BY, Toyama BH, Wille H, Colby DW, Collins SR,
May BC, Prusiner SB, Weissman J, Shoichet BK (2008)
Small-molecule aggregates inhibit amyloid polymerization. Nat Chem Biol 4, 197-199.
Lee JH, Byeon SR, Lim SJ, Oh SJ, Moon DH, Yoo KH,
Chung BY, Kim DJ (2008) Synthesis and evaluation of stilbenylbenzoxazole and stilbenylbenzothiazole derivatives
for detecting beta-amyloid fibrils. Bioorg Med Chem Lett
18, 1534-1537.
Velkova A, Tatarek-Nossol M, Andreetto E, Kapurniotu
A (2008) Exploiting cross-amyloid interactions to inhibit
protein aggregation but not function: Nanomolar affinity
inhibition of insulin aggregation by an IAPP mimic. Angew
Chem Int Ed Engl 47, 7114-7118.
Wang H, Duennwald ML, Roberts BE, Rozeboom LM,
Zhang YL, Steele AD, Krishnan R, Su LJ, Griffin D,
Mukhopadhyay S, Hennessy EJ, Weigele P, Blanchard BJ,
King J, Deniz AA, Buchwald SL, Ingram VM, Lindquist
S, Shorter J (2008) Direct and selective elimination of specific prions and amyloids by 4,5-dianilinophthalimide and
analogs. Proc Natl Acad Sci U S A 105, 7159-7164.
Wisniewski T, Sadowski M (2008) Preventing betaamyloid fibrillization and deposition: Beta-sheet breakers
and pathological chaperone inhibitors. BMC Neurosci
9(Suppl 2), S5.
Barthel A, Trieschmann L, Strohl D, Kluge R, Bohm G,
Csuk R (2009) Synthesis of dimeric quinazolin-2-one,
1,4-benzodiazepin-2-one, and isoalloxazine compounds as
92
[1107]
[1108]
[1109]
[1110]
[1111]
[1112]
[1113]
[1114]
[1115]
[1116]
[1117]
[1118]
[1119]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
inhibitors of amyloid peptides association. Arch Pharm
(Weinheim) 342, 445-452.
Campiglia P, Scrima M, Grimaldi M, Cioffi G, Bertamino
A, Sala M, Aquino C, Gomez-Monterrey I, Grieco
P, Novellino E, D’Ursi AM (2009) A new series of
1,3-dihidro-imidazo[1,5-c]thiazole-5,7-dione derivatives:
Synthesis and interaction with Abeta(25-35) amyloid peptide. Chem Biol Drug Des 74, 224-233.
Csuk R, Barthel A, Raschke C, Kluge R, Strohl D, Trieschmann L, Bohm G (2009) Synthesis of monomeric and
dimeric acridine compounds as potential therapeutics in
Alzheimer and prion diseases. Arch Pharm (Weinheim)
342, 699-709.
Frydman-Marom A, Rechter M, Shefler I, Bram Y, Shalev
DE, Gazit E (2009) Cognitive-performance recovery of
Alzheimer’s disease model mice by modulation of early
soluble amyloidal assemblies. Angew Chem Int Ed Engl
48, 1981-1986.
Giordano C, Masi A, Pizzini A, Sansone A, Consalvi V,
Chiaraluce R, Lucente G (2009) Synthesis and activity
of fibrillogenesis peptide inhibitors related to the 17-21
beta-amyloid sequence. Eur J Med Chem 44, 179-189.
Grillo-Bosch D, Carulla N, Cruz M, Sanchez L, PujolPina R, Madurga S, Rabanal F, Giralt E (2009)
Retro-enantio N-methylated peptides as beta-amyloid
aggregation inhibitors. ChemMedChem 4, 1488-1494.
Madine J, Wang X, Brown DR, Middleton DA (2009)
Evaluation of beta-alanine- and GABA-substituted peptides as inhibitors of disease-linked protein aggregation.
Chembiochem 10, 1982-1987.
Dolphin GT, Renaudet O, Ouberai M, Dumy P, Garcia
J, Reymond JL (2009) Phenolic oxime oligomers inhibit
Alzheimer’s amyloid fibril formation and disaggregate fibrils in vitro. Chembiochem 10, 1325-1329.
Catto M, Aliano R, Carotti A, Cellamare S, Palluotto F, Purgatorio R, De SA, Campagna F (2010)
Design, synthesis and biological evaluation of
indane-2-arylhydrazinylmethylene-1,3-diones
and
indol-2-aryldiazenylmethylene-3-ones as beta-amyloid
aggregation inhibitors. Eur J Med Chem 45, 1359-1366.
Matharu B, El-Agnaf O, Razvi A, Austen BM (2010)
Development of retro-inverso peptides as anti-aggregation
drugs for beta-amyloid in Alzheimer’s disease. Peptides
31, 1866-1872.
Suzuki M, Takahashi T, Sato J, Mie M, Kobatake E, Mihara
H (2010) Designed short peptides that form amyloid-like
fibrils in coassembly with amyloid beta-peptide (Abeta)
decrease the toxicity of Abeta to neuronal PC12 cells.
Chembiochem 11, 1525-1530.
Zhou Y, Jiang C, Zhang Y, Liang Z, Liu W, Wang L, Luo
C, Zhong T, Sun Y, Zhao L, Xie X, Jiang H, Zhou N, Liu
D, Liu H (2010) Structural optimization and biological
evaluation of substituted bisphenol A derivatives as betaamyloid peptide aggregation inhibitors. J Med Chem 53,
5449-5466.
Ladiwala AR, Dordick JS, Tessier PM (2011) Aromatic
small molecules remodel toxic soluble oligomers of amyloid beta through three independent pathways. J Biol Chem
286, 3209-3218.
Ortega A, Rincon A, Jimenez-Aliaga KL, Bermejo-Bescos
P, Martin-Aragon S, Molina MT, Csaky AG (2011) Synthesis and evaluation of arylquinones as BACE1 inhibitors,
beta-amyloid peptide aggregation inhibitors, and destabilizers of preformed beta-amyloid fibrils. Bioorg Med Chem
Lett 21, 2183-2187.
[1120]
[1121]
[1122]
[1123]
[1124]
[1125]
[1126]
[1127]
[1128]
[1129]
[1130]
[1131]
[1132]
[1133]
[1134]
[1135]
Ryan TM, Griffin MD, Teoh CL, Ooi J, Howlett GJ (2011)
High-affinity amphipathic modulators of amyloid fibril
nucleation and elongation. J Mol Biol 406, 416-429.
Ryan TM, Griffin MD, Bailey MF, Schuck P, Howlett GJ
(2011) NBD-labeled phospholipid accelerates apolipoprotein C-II amyloid fibril formation but is not incorporated
into mature fibrils. Biochemistry 50, 9579-9586.
Frydman-Marom A, Shaltiel-Karyo R, Moshe S, Gazit E
(2011) The generic amyloid formation inhibition effect of
a designed small aromatic beta-breaking peptide. Amyloid
18, 119-127.
Lukiw WJ (2012) Amyloid beta (Abeta) peptide modulators and other current treatment strategies for Alzheimer’s
disease (AD). Expert Opin Emerg Drugs 17, 43-60.
Di Santo R, Costi R, Cuzzucoli CG, Pescatori L, Rosi F,
Scipione L, Celona D, Vertechy M, Ghirardi O, Piovesan
P, Marzi M, Caccia S, Guiso G, Giorgi F, Minetti P (2012)
Design, synthesis and structure-activity relationship of NAryl-naphthylamine derivatives as amyloid aggregation
inhibitors. J Med Chem 55, 8538-8548.
Cheng PN, Liu C, Zhao M, Eisenberg D, Nowick JS (2012)
Amyloid beta-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity. Nat Chem 4, 927-933.
Huang L, Lu C, Sun Y, Mao F, Luo Z, Su T,
Jiang H, Shan W, Li X (2012) Multi-target-directed
benzylidene-indanone derivatives: Anti-beta amyloid
(Abeta) aggregation, antioxidant, metal chelation and
monoamine oxidase B (MAO-B) inhibition properties
against Alzheimer’s disease. J Med Chem 55, 8483-8492.
Liu R, Su R, Liang M, Huang R, Wang M, Qi W, He Z
(2012) Physicochemical strategies for inhibition of amyloid fibril formation: An overview of recent advances. Curr
Med Chem 19, 4157-4174.
Ryan TM, Friedhuber A, Lind M, Howlett GJ, Masters C, Roberts BR (2012) Small amphipathic molecules
modulate secondary structure and amyloid fibril-forming
kinetics of Alzheimer disease peptide Abeta(1-42). J Biol
Chem 287, 16947-16954.
Lopez LC, Dos-Reis S, Espargaro A, Carrodeguas JA,
Maddelein ML, Ventura S, Sancho J (2012) Discovery of
novel inhibitors of amyloid beta-peptide 1-42 aggregation.
J Med Chem 55, 9521-9530.
Guo JT, Xu Y (2006) Amyloid fibril structure modeling
using protein threading and molecular dynamics simulations. Methods Enzymol 412, 300-314.
Guo JT, Xu Y (2008) Towards modeling of amyloid fibril
structures. Front Biosci 13, 4039-4050.
Esteras-Chopo A, Morra G, Moroni E, Serrano L, Lopez
de la PM, Colombo G (2008) A molecular dynamics study
of the interaction of D-peptide amyloid inhibitors with
their target sequence reveals a potential inhibitory pharmacophore conformation. J Mol Biol 383, 266-280.
Wu C, Wang Z, Lei H, Duan Y, Bowers MT, Shea JE (2008)
The binding of thioflavin T and its neutral analog BTA1 to protofibrils of the Alzheimer’s disease Abeta(16-22)
peptide probed by molecular dynamics simulations. J Mol
Biol 384, 718-729.
Wu C, Murray MM, Bernstein SL, Condron MM, Bitan
G, Shea JE, Bowers MT (2009) The structure of Abeta42
C-terminal fragments probed by a combined experimental
and theoretical study. J Mol Biol 387, 492-501.
Chebaro Y, Mousseau N, Derreumaux P (2009) Structures and thermodynamics of Alzheimer’s amyloid-beta
Abeta(16-35) monomer and dimer by replica exchange
molecular dynamics simulations: Implication for full-
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1136]
[1137]
[1138]
[1139]
[1140]
[1141]
[1142]
[1143]
[1144]
[1145]
[1146]
[1147]
[1148]
[1149]
[1150]
length Abeta fibrillation. J Phys Chem B 113, 76687675.
Chebaro Y, Derreumaux P (2009) Targeting the early steps
of Abeta16-22 protofibril disassembly by N-methylated
inhibitors: A numerical study. Proteins 75, 442452.
Convertino M, Pellarin R, Catto M, Carotti A, Caflisch
A (2009) 9,10-Anthraquinone hinders beta-aggregation:
How does a small molecule interfere with Abeta-peptide
amyloid fibrillation? Protein Sci 18, 792-800.
Frydman-Marom A, Convertino M, Pellarin R, Lampel
A, Shaltiel-Karyo R, Segal D, Caflisch A, Shalev DE,
Gazit E (2011) Structural basis for inhibiting beta-amyloid
oligomerization by a non-coded beta-breaker-substituted
endomorphin analogue. ACS Chem Biol 6, 1265-1276.
Stempler S, Levy-Sakin M, Frydman-Marom A, Amir Y,
Scherzer-Attali R, Buzhansky L, Gazit E, Senderowitz H
(2011) Quantitative structure-activity relationship analysis
of beta-amyloid aggregation inhibitors. J Comput Aided
Mol Des 25, 135-144.
Wise-Scira O, Xu L, Kitahara T, Perry G, Coskuner O
(2011) Amyloid-beta peptide structure in aqueous solution
varies with fragment size. J Chem Phys 135, 205101.
Convertino M, Vitalis A, Caflisch A (2011) Disordered
binding of small molecules to Abeta(12-28). J Biol Chem
286, 41578-41588.
Chebaro Y, Jiang P, Zang T, Mu Y, Nguyen PH, Mousseau
N, Derreumaux P (2012) Structures of abeta17-42 trimers
in isolation and with five small-molecule drugs using a
hierarchical computational procedure. J Phys Chem B 116,
8412-8422.
Novick PA, Lopes DH, Branson KM, Esteras-Chopo A,
Graef IA, Bitan G, Pande VS (2012) Design of betaamyloid aggregation inhibitors from a predicted structural
motif. J Med Chem 55, 3002-3010.
Srivastava A, Balaji PV (2012) Size, orientation and organization of oligomers that nucleate amyloid fibrils: Clues
from MD simulations of pre-formed aggregates. Biochim
Biophys Acta 1824, 963-973.
Greenberg SM, Rosand J, Schneider AT, Creed PL, Gandy
SE, Rovner B, Fitzsimmons BF, Smith EE, Edip GM,
Schwab K, Laurin J, Garceau D (2006) A phase 2 study of
tramiprosate for cerebral amyloid angiopathy. Alzheimer
Dis Assoc Disord 20, 269-274.
Wright TM (2006) Tramiprosate. Drugs Today (Barc) 42,
291-298.
Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M,
Azzi M, Lacombe D, Kong X, Aman A, Laurin J, Szarek
WA, Tremblay P (2007) Targeting soluble Abeta peptide
with Tramiprosate for the treatment of brain amyloidosis.
Neurobiol Aging 28, 537-547.
Gauthier S, Aisen PS, Ferris SH, Saumier D, Duong A,
Haine D, Garceau D, Suhy J, Oh J, Lau W, Sampalis
J (2009) Effect of tramiprosate in patients with mild-tomoderate Alzheimer’s disease: Exploratory analyses of the
MRI sub-group of the Alphase study. J Nutr Health Aging
13, 550-557.
Saumier D, Aisen PS, Gauthier S, Vellas B, Ferris SH,
Duong A, Suhy J, Oh J, Lau W, Garceau D, Haine D,
Sampalis J (2009) Lessons learned in the use of volumetric MRI in therapeutic trials in Alzheimer’s disease: The
ALZHEMED (Tramiprosate) experience. J Nutr Health
Aging 13, 370-372.
Saumier D, Duong A, Haine D, Garceau D, Sampalis J
(2009) Domain-specific cognitive effects of tramiprosate
[1151]
[1152]
[1153]
[1154]
[1155]
[1156]
[1157]
[1158]
[1159]
[1160]
[1161]
[1162]
[1163]
[1164]
93
in patients with mild to moderate Alzheimer’s disease:
ADAS-cog subscale results from the Alphase Study. J Nutr
Health Aging 13, 808-812.
Aisen PS, Gauthier S, Ferris SH, Saumier D, Haine D,
Garceau D, Duong A, Suhy J, Oh J, Lau WC, Sampalis
J (2011) Tramiprosate in mild-to-moderate Alzheimer’s
disease - a randomized, double-blind, placebo-controlled,
multi-centre study (the Alphase Study). Arch Med Sci 7,
102-111.
Swanoski MT (2009) Homotaurine: A failed drug for
Alzheimer’s disease and now a nutraceutical for memory protection. Am J Health Syst Pharm 66, 19501953.
Adessi C, Frossard MJ, Boissard C, Fraga S, Bieler S,
Ruckle T, Vilbois F, Robinson SM, Mutter M, Banks WA,
Soto C (2003) Pharmacological profiles of peptide drug
candidates for the treatment of Alzheimer’s disease. J Biol
Chem 278, 13905-13911.
Uryu S, Tokuhiro S, Murasugi T, Oda T (2002) A
novel compound, RS-1178, specifically inhibits neuronal
cell death mediated by beta-amyloid-induced macrophage
activation in vitro. Brain Res 946, 298-306.
Nakagami Y, Nishimura S, Murasugi T, Kaneko I, Meguro
M, Marumoto S, Kogen H, Koyama K, Oda T (2002)
A novel beta-sheet breaker, RS-0406, reverses amyloid
beta-induced cytotoxicity and impairment of long-term
potentiation in vitro. Br J Pharmacol 137, 676-682.
Nakagami Y, Nishimura S, Murasugi T, Kubo T, Kaneko
I, Meguro M, Marumoto S, Kogen H, Koyama K, Oda
T (2002) A novel compound RS-0466 reverses betaamyloid-induced cytotoxicity through the Akt signaling
pathway in vitro. Eur J Pharmacol 457, 11-17.
Walsh DM, Townsend M, Podlisny MB, Shankar GM,
Fadeeva JV, El AO, Hartley DM, Selkoe DJ (2005) Certain inhibitors of synthetic amyloid beta-peptide (Abeta)
fibrillogenesis block oligomerization of natural Abeta and
thereby rescue long-term potentiation. J Neurosci 25,
2455-2462.
O’Hare E, Scopes DI, Treherne JM, Norwood K, Spanswick D, Kim EM (2010) RS-0406 arrests amyloid-beta
oligomer-induced behavioural deterioration in vivo. Behav
Brain Res 210, 32-37.
Rodrigue KM, Kennedy KM, Park DC (2009) Betaamyloid deposition and the aging brain. Neuropsychol Rev
19, 436-450.
Rodrigue KM, Kennedy KM, Devous MD, Rieck JR,
Hebrank AC, Diaz-Arrastia R, Mathews D, Park DC
(2012) beta-Amyloid burden in healthy aging: Regional
distribution and cognitive consequences. Neurology 78,
387-395.
Cohen RM (2007) The application of positron-emitting
molecular imaging tracers in Alzheimer’s disease. Mol
Imaging Biol 9, 204-216.
Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML,
Klunk WE (2003) Synthesis and evaluation of 11C-labeled
6-substituted 2-arylbenzothiazoles as amyloid imaging
agents. J Med Chem 46, 2740-2754.
Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s
disease. Lancet 368, 387-403.
Fagan AM, Mintun MA, Mach RH, Lee SY, Dence
CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE,
Mathis CA, Dekosky ST, Morris JC, Holtzman DM (2006)
Inverse relation between in vivo amyloid imaging load and
cerebrospinal fluid Abeta42 in humans. Ann Neurol 59,
512-519.
94
[1165]
[1166]
[1167]
[1168]
[1169]
[1170]
[1171]
[1172]
[1173]
[1174]
[1175]
[1176]
[1177]
[1178]
[1179]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Quigley H, Colloby SJ, O’Brien JT (2011) PET imaging of brain amyloid in dementia: A review. Int J Geriatr
Psychiatry 26, 991-999.
Tarawneh R, Holtzman DM (2010) Biomarkers in
translational research of Alzheimer’s disease. Neuropharmacology 59, 310-322.
Forsberg A, Almkvist O, Engler H, Wall A, Langstrom B,
Nordberg A (2010) High PIB retention in Alzheimer’s disease is an early event with complex relationship with CSF
biomarkers and functional parameters. Curr Alzheimer Res
7, 56-66.
Grimmer T, Henriksen G, Wester HJ, Forstl H, Klunk WE,
Mathis CA, Kurz A, Drzezga A (2009) Clinical severity of
Alzheimer’s disease is associated with PIB uptake in PET.
Neurobiol Aging 30, 1902-1909.
Ances BM, Benzinger TL, Christensen JJ, Thomas J,
Venkat R, Teshome M, Aldea P, Fagan AM, Holtzman DM,
Morris JC, Clifford DB (2012) 11C-PiB imaging of human
immunodeficiency virus-associated neurocognitive disorder. Arch Neurol 69, 72-77.
Kung HF (2012) The beta-amyloid hypotheis in
Alzheimer’s disease: Seeing is believing. ACS Med Chem
Lett 3, 265-267.
Ossenkoppele R, van Berckel BN, Prins ND (2011)
Amyloid imaging in prodromal Alzheimer’s disease.
Alzheimers Res Ther 3, 26.
Ossenkoppele R, Tolboom N, Foster-Dingley JC, Adriaanse SF, Boellaard R, Yaqub M, Windhorst AD,
Barkhof F, Lammertsma AA, Scheltens P, van der Flier
WM, van Berckel BN (2012) Longitudinal imaging of
Alzheimer pathology using [(11)C]PIB, [(18)F]FDDNP
and [(18)F]FDG PET. Eur J Nucl Med Mol Imaging 39,
990-1000.
Ossenkoppele R, Zwan MD, Tolboom N, van Assema
DM, Adriaanse SF, Kloet RW, Boellaard R, Windhorst
AD, Barkhof F, Lammertsma AA, Scheltens P, van der
Flier WM, van Berckel BN (2012) Amyloid burden and
metabolic function in early-onset Alzheimer’s disease:
Parietal lobe involvement. Brain 135, 2115-2125.
Small GW, Siddarth P, Kepe V, Ercoli LM, Burggren AC,
Bookheimer SY, Miller KJ, Kim J, Lavretsky H, Huang
SC, Barrio JR (2012) Prediction of cognitive decline by
positron emission tomography of brain amyloid and tau.
Arch Neurol 69, 215-222.
Herholz K (2012) Imaging cerebral amyloid plaques: Clinical perspective. Lancet Neurol 11, 652-653.
Driscoll I, Troncoso JC, Rudow G, Sojkova J, Pletnikova
O, Zhou Y, Kraut MA, Ferrucci L, Mathis CA, Klunk WE,
O’Brien RJ, Davatzikos C, Wong DF, Resnick SM (2012)
Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment
of plaques. Acta Neuropathol, doi: 10.1007/s00401-0121025-1
Serdons K, Verduyckt T, Vanderghinste D, Borghgraef P,
Cleynhens J, Van Leuven F, Kung H, Bormans G, Verbruggen A (2009) 11C-labelled PIB analogues as potential
tracer agents for in vivo imaging of amyloid beta in
Alzheimer’s disease. Eur J Med Chem 44, 1415-1426.
Serdons K, Verbruggen A, Bormans GM (2009) Developing new molecular imaging probes for PET. Methods 48,
104-111.
Choi SR, Golding G, Zhuang Z, Zhang W, Lim N, Hefti
F, Benedum TE, Kilbourn MR, Skovronsky D, Kung HF
(2009) Preclinical properties of 18F-AV-45: A PET agent
for Abeta plaques in the brain. J Nucl Med 50, 1887-1894.
[1180]
[1181]
[1182]
[1183]
[1184]
[1185]
[1186]
[1187]
[1188]
[1189]
[1190]
[1191]
[1192]
Choi SR, Schneider JA, Bennett DA, Beach TG, Bedell
BJ, Zehntner SP, Krautkramer MJ, Kung HF, Skovronsky
DM, Hefti F, Clark CM (2012) Correlation of amyloid
PET ligand florbetapir F 18 binding with abeta aggregation
and neuritic plaque deposition in postmortem brain tissue.
Alzheimer Dis Assoc Disord 26, 8-16.
Kung HF, Choi SR, Qu W, Zhang W, Skovronsky D (2010)
18F stilbenes and styrylpyridines for PET imaging of A
beta plaques in Alzheimer’s disease: A miniperspective.
J Med Chem 53, 933-941.
Lin KJ, Hsu WC, Hsiao IT, Wey SP, Jin LW, Skovronsky
D, Wai YY, Chang HP, Lo CW, Yao CH, Yen TC, Kung MP
(2010) Whole-body biodistribution and brain PET imaging
with [18F]AV-45, a novel amyloid imaging agent–a pilot
study. Nucl Med Biol 37, 497-508.
Liu Y, Zhu L, Plossl K, Choi SR, Qiao H, Sun X, Li
S, Zha Z, Kung HF (2010) Optimization of automated
radiosynthesis of [18F]AV-45: A new PET imaging agent
for Alzheimer’s disease. Nucl Med Biol 37, 917-925.
Okamura N, Yanai K (2010) Florbetapir (18F), a PET
imaging agent that binds to amyloid plaques for the potential detection of Alzheimer’s disease. IDrugs 13, 890-899.
Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont
V, Ravert HT, Dannals RF, Nandi A, Brasic JR, Ye W,
Hilton J, Lyketsos C, Kung HF, Joshi AD, Skovronsky
DM, Pontecorvo MJ (2010) In vivo imaging of amyloid
deposition in Alzheimer disease using the radioligand 18FAV-45 (florbetapir [corrected] F 18). J Nucl Med 51, 913920.
Yao CH, Lin KJ, Weng CC, Hsiao IT, Ting YS, Yen
TC, Jan TR, Skovronsky D, Kung MP, Wey SP (2010)
GMP-compliant automated synthesis of [(18)F]AV-45
(Florbetapir F 18) for imaging beta-amyloid plaques in
human brain. Appl Radiat Isot 68, 2293-2297.
Lister-James J, Pontecorvo MJ, Clark C, Joshi AD, Mintun
MA, Zhang W, Lim N, Zhuang Z, Golding G, Choi
SR, Benedum TE, Kennedy P, Hefti F, Carpenter AP,
Kung HF, Skovronsky DM (2011) Florbetapir f-18: A
histopathologically validated Beta-amyloid positron emission tomography imaging agent. Semin Nucl Med 41,
300-304.
Carome M, Wolfe S (2011) Florbetapir-PET imaging and
postmortem beta-amyloid pathology. JAMA 305, 18571858.
Clark CM, Schneider JA, Bedell BJ, Beach TG, Bilker
WB, Mintun MA, Pontecorvo MJ, Hefti F, Carpenter AP,
Flitter ML, Krautkramer MJ, Kung HF, Coleman RE,
Doraiswamy PM, Fleisher AS, Sabbagh MN, Sadowsky
CH, Reiman EP, Zehntner SP, Skovronsky DM (2011) Use
of florbetapir-PET for imaging beta-amyloid pathology.
JAMA 305, 275-283.
Fleisher AS, Chen K, Liu X, Roontiva A, Thiyyagura P,
Ayutyanont N, Joshi AD, Clark CM, Mintun MA, Pontecorvo MJ, Doraiswamy PM, Johnson KA, Skovronsky
DM, Reiman EM (2011) Using positron emission tomography and florbetapir F18 to image cortical amyloid in
patients with mild cognitive impairment or dementia due
to Alzheimer disease. Arch Neurol 68, 1404-1411.
Frisoni GB (2011) PET and 18F ligands in the diagnosis
of Alzheimer’s disease. Lancet Neurol 10, 397-399.
Joshi AD, Pontecorvo MJ, Clark CM, Carpenter AP, Jennings DL, Sadowsky CH, Adler LP, Kovnat KD, Seibyl
JP, Arora A, Saha K, Burns JD, Lowrey MJ, Mintun
MA, Skovronsky DM (2012) Performance characteristics
of amyloid PET with florbetapir F 18 in patients with
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1193]
[1194]
[1195]
[1196]
[1197]
[1198]
[1199]
[1200]
[1201]
[1202]
[1203]
Alzheimer’s disease and cognitively normal subjects. J
Nucl Med 53, 378-384.
Saint-Aubert L, Planton M, Hannequin D, Albucher JF,
Delisle MB, Payoux P, Hitzel A, Viallard G, Peran P, Campion D, Laquerriere A, Barbeau EJ, Puel M, Raposo N,
Chollet F, Pariente J (2012) Amyloid imaging with AV45
(18F-florbetapir) in a cognitively normal AbetaPP duplication carrier. J Alzheimers Dis 28, 877-883.
Sabbagh MN, Fleisher A, Chen K, Rogers J, Berk C,
Reiman E, Pontecorvo M, Mintun M, Skovronsky D,
Jacobson SA, Sue LI, Liebsack C, Charney AS, Cole L,
Belden C, Beach TG (2011) Positron emission tomography
and neuropathologic estimates of fibrillar amyloid-beta in
a patient with Down syndrome and Alzheimer disease.
Arch Neurol 68, 1461-1466.
Huang KL, Lin KJ, Ho MY, Chang YJ, Chang CH, Wey
SP, Hsieh CJ, Yen TC, Hsiao IT, Lee TH (2012) Amyloid deposition after cerebral hypoperfusion: Evidenced
on [(18)F]AV-45 positron emission tomography. J Neurol
Sci 319, 124-129.
Hsiao IT, Huang CC, Hsieh CJ, Hsu WC, Wey SP, Yen TC,
Kung MP, Lin KJ (2012) Correlation of early-phase 18Fflorbetapir (AV-45/Amyvid) PET images to FDG images:
Preliminary studies. Eur J Nucl Med Mol Imaging 39, 613620.
Camus V, Payoux P, Barre L, Desgranges B, Voisin T,
Tauber C, La JR, Tafani M, Hommet C, Chetelat G, Mondon K, de LS, V, Cottier JP, Beaufils E, Ribeiro MJ, Gissot
V, Vierron E, Vercouillie J, Vellas B, Eustache F, Guilloteau D (2012) Using PET with 18F-AV-45 (florbetapir)
to quantify brain amyloid load in a clinical environment.
Eur J Nucl Med Mol Imaging 39, 621-631.
Newberg AB, Arnold SE, Wintering N, Rovner BW, Alavi
A (2012) Initial clinical comparison of 18F-Florbetapir
and 18F-FDG PET in patients with Alzheimer disease and
controls. J Nucl Med 53, 902-907.
Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, Fleisher AS, Reiman EM,
Sabbagh MN, Sadowsky CH, Schneider JA, Arora A, Carpenter AP, Flitter ML, Joshi AD, Krautkramer MJ, Lu M,
Mintun MA, Skovronsky DM (2012) Cerebral PET with
florbetapir compared with neuropathology at autopsy for
detection of neuritic amyloid-beta plaques: A prospective
cohort study. Lancet Neurol 11, 669-678.
Kingwell K (2012) Alzheimer disease: Florbetapir-a useful tool to image amyloid load and predict cognitive decline
in Alzheimer disease. Nat Rev Neurol 8, 471.
Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL,
O’Keefe G, Tochon-Danguy H, Chan G, Berlangieri SU,
Jones G, Ckinson-Rowe KL, Kung HP, Zhang W, Kung
MP, Skovronsky D, Dyrks T, Holl G, Krause S, Friebe
M, Lehman L, Lindemann S, Dinkelborg LM, Masters
CL, Villemagne VL (2008) Imaging of amyloid beta in
Alzheimer’s disease with 18F-BAY94-9172, a novel PET
tracer: Proof of mechanism. Lancet Neurol 7, 129-135.
Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P,
Buerger K, Hiemeyer F, Wittemer-Rump SM, Seibyl J,
Reininger C, Sabri O (2011) Cerebral amyloid-beta PET
with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: A multicentre phase 2 diagnostic
study. Lancet Neurol 10, 424-435.
Barthel H, Luthardt J, Becker G, Patt M, Hammerstein
E, Hartwig K, Eggers B, Sattler B, Schildan A, Hesse S,
Meyer PM, Wolf H, Zimmermann T, Reischl J, Rohde
B, Gertz HJ, Reininger C, Sabri O (2011) Individualized
[1204]
[1205]
[1206]
[1207]
[1208]
[1209]
[1210]
[1211]
[1212]
[1213]
[1214]
[1215]
[1216]
95
quantification of brain beta-amyloid burden: Results of
a proof of mechanism phase 0 florbetaben PET trial in
patients with Alzheimer’s disease and healthy controls.
Eur J Nucl Med Mol Imaging 38, 1702-1714.
Barthel H, Sabri O (2011) Florbetaben to trace amyloidbeta in the Alzheimer brain by means of PET. J Alzheimers
Dis 26(Suppl 3), 117-121.
Herholz K, Ebmeier K (2011) Clinical amyloid imaging
in Alzheimer’s disease. Lancet Neurol 10, 667-670.
Vallabhajosula S (2011) Positron emission tomography
radiopharmaceuticals for imaging brain Beta-amyloid.
Semin Nucl Med 41, 283-299.
Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska
S, Jones G, O’Keefe G, Ackerman U, Tochon-Danguy
H, Chan JG, Reininger CB, Fels L, Putz B, Rohde B,
Masters CL, Rowe CC (2011) Amyloid imaging with
(18)F-florbetaben in Alzheimer disease and other dementias. J Nucl Med 52, 1210-1217.
Villemagne VL, Okamura N, Pejoska S, Drago J, Mulligan
RS, Chetelat G, O’Keefe G, Jones G, Kung HF, Pontecorvo
M, Masters CL, Skovronsky DM, Rowe CC (2012) Differential diagnosis in Alzheimer’s disease and dementia with
Lewy bodies via VMAT2 and amyloid imaging. Neurodegener Dis 10, 161-165.
Wang H, Shi H, Yu H, Jiang S, Tang G (2011) Facile and
rapid one-step radiosynthesis of [(18)F]BAY94-9172 with
a new precursor. Nucl Med Biol 38, 121-127.
O’Keefe GJ, Saunder TH, Ng S, Ackerman U, TochonDanguy HJ, Chan JG, Gong S, Dyrks T, Lindemann S,
Holl G, Dinkelborg L, Villemagne V, Rowe CC (2009)
Radiation dosimetry of beta-amyloid tracers 11C-PiB and
18F-BAY94-9172. J Nucl Med 50, 309-315.
Villemagne VL, Mulligan RS, Pejoska S, Ong K, Jones
G, O’Keefe G, Chan JG, Young K, Tochon-Danguy H,
Masters CL, Rowe CC (2012) Comparison of (11)C-PiB
and (18)F-florbetaben for Abeta imaging in ageing and
Alzheimer’s disease. Eur J Nucl Med Mol Imaging 39,
983-989.
Schipke CG, Peters O, Heuser I, Grimmer T, Sabbagh
MN, Sabri O, Hock C, Kunz M, Kuhlmann J, Reininger
C, Blankenburg M (2012) Impact of beta-amyloid-specific
florbetaben PET imaging on confidence in early diagnosis
of Alzheimer’s disease. Dement Geriatr Cogn Disord 33,
416-422.
Nelissen N, Van LK, Thurfjell L, Owenius R, Vandenbulcke M, Koole M, Bormans G, Brooks DJ, Vandenberghe R
(2009) Phase 1 study of the Pittsburgh compound B derivative 18F-flutemetamol in healthy volunteers and patients
with probable Alzheimer disease. J Nucl Med 50, 12511259.
Vandenberghe R, Van LK, Ivanoiu A, Salmon E, Bastin
C, Triau E, Hasselbalch S, Law I, Andersen A, Korner A,
Minthon L, Garraux G, Nelissen N, Bormans G, Buckley
C, Owenius R, Thurfjell L, Farrar G, Brooks DJ (2010)
18F-flutemetamol amyloid imaging in Alzheimer disease
and mild cognitive impairment: A phase 2 trial. Ann Neurol
68, 319-329.
Thomas BA, Erlandsson K, Modat M, Thurfjell L, Vandenberghe R, Ourselin S, Hutton BF (2011) The importance of
appropriate partial volume correction for PET quantification in Alzheimer’s disease. Eur J Nucl Med Mol Imaging
38, 1104-1119.
Wolk DA, Grachev ID, Buckley C, Kazi H, Grady MS,
Trojanowski JQ, Hamilton RH, Sherwin P, McLain
R, Arnold SE (2011) Association between in vivo
96
[1217]
[1218]
[1219]
[1220]
[1221]
[1222]
[1223]
[1224]
[1225]
[1226]
[1227]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical
histopathology. Arch Neurol 68, 1398-1403.
Thurfjell L, Lotjonen J, Lundqvist R, Koikkalainen
J, Soininen H, Waldemar G, Brooks DJ, Vandenberghe R (2012) Combination of biomarkers: PET
[18F]flutemetamol imaging and structural MRI in dementia and mild cognitive impairment. Neurodegener Dis 10,
246-249.
Vandenberghe R, Nelissen N, Salmon E, Ivanoiu A, Hasselbalch S, Andersen A, Korner A, Minthon L, Brooks DJ,
Van LK, Dupont P (2012) Binary classification of (18)Fflutemetamol PET using machine learning: Comparison
with visual reads and structural MRI. Neuroimage 64C,
517-525.
Snellman A, Rokka J, Lopez-Picon FR, Eskola O, Wilson
I, Farrar G, Scheinin M, Solin O, Rinne JO, HaaparantaSolin M (2012) Pharmacokinetics of [(18)F]flutemetamol
in wild-type rodents and its binding to beta amyloid
deposits in a mouse model of Alzheimer’s disease. Eur
J Nucl Med Mol Imaging 39, 1784-1795.
Jureus A, Swahn BM, Sandell J, Jeppsson F, Johnson
AE, Johnstrom P, Neelissen JA, Sunnemark D, Farde L,
Svensson SP (2010) Characterization of AZD4694, a novel
fluorinated Abeta plaque neuroimaging PET radioligand.
J Neurochem 114, 784-794.
Brockschnieder D, Schmitt-Willich H, Heinrich T, Varrone
A, Gulyas B, Toth M, Andersson J, Boemer U, Krause S,
Friebe M, Dinkelborg L, Halldin C, Dyrks T (2012) Preclinical characterization of a novel class of 18F-Labeled
PET tracers for amyloid-beta. J Nucl Med 53, 1794-1801.
Furukawa K, Okamura N, Tashiro M, Waragai M, Furumoto S, Iwata R, Yanai K, Kudo Y, Arai H (2010) Amyloid
PET in mild cognitive impairment and Alzheimer’s disease with BF-227: Comparison to FDG-PET. J Neurol 257,
721-727.
Shao H, Okamura N, Sugi K, Furumoto S, Furukawa K,
Tashiro M, Iwata R, Matsuda H, Kudo Y, Arai H, Fukuda H,
Yanai K (2010) Voxel-based analysis of amyloid positron
emission tomography probe [C]BF-227 uptake in mild
cognitive impairment and alzheimer’s disease. Dement
Geriatr Cogn Disord 30, 101-111.
Kaneta T, Okamura N, Minoshima S, Furukawa K, Tashiro
M, Furumoto S, Iwata R, Fukuda H, Takahashi S, Yanai
K, Kudo Y, Arai H (2011) A modified method of 3D-SSP
analysis for amyloid PET imaging using [(11)C]BF-227.
Ann Nucl Med 25, 732-739.
Tomita N, Furukawa K, Okamura N, Tashiro M, Une K,
Furumoto S, Iwata R, Yanai K, Kudo Y, Arai H (2012)
Brain accumulation of amyloid beta protein visualized by
positron emission tomography and BF-227 in Alzheimer’s
disease patients with or without diabetes mellitus. Geriatr Gerontol Int, doi: 10.1111/j.1447-0594.2012.00880.x
[Epub ahead of print].
Fodero-Tavoletti MT, Mulligan RS, Okamura N, Furumoto
S, Rowe CC, Kudo Y, Masters CL, Cappai R, Yanai K,
Villemagne VL (2009) In vitro characterisation of BF227
binding to alpha-synuclein/Lewy bodies. Eur J Pharmacol
617, 54-58.
Kikuchi A, Takeda A, Okamura N, Tashiro M, Hasegawa
T, Furumoto S, Kobayashi M, Sugeno N, Baba T, Miki Y,
Mori F, Wakabayashi K, Funaki Y, Iwata R, Takahashi
S, Fukuda H, Arai H, Kudo Y, Yanai K, Itoyama Y
(2010) In vivo visualization of alpha-synuclein deposition
by carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-
[1228]
[1229]
[1230]
[1231]
[1232]
[1233]
[1234]
[1235]
[1236]
[1237]
[1238]
[1239]
yl)ethenyl]-6-[2-(fluoro)ethoxy]benzoxazole
positron
emission tomography in multiple system atrophy. Brain
133, 1772-1778.
Okamura N, Shiga Y, Furumoto S, Tashiro M, Tsuboi Y,
Furukawa K, Yanai K, Iwata R, Arai H, Kudo Y, Itoyama
Y, Doh-ura K (2010) In vivo detection of prion amyloid
plaques using [(11)C]BF-227 PET. Eur J Nucl Med Mol
Imaging 37, 934-941.
Kung MP, Hou C, Zhuang ZP, Skovronsky D, Kung HF
(2004) Binding of two potential imaging agents targeting
amyloid plaques in postmortem brain tissues of patients
with Alzheimer’s disease. Brain Res 1025, 98-105.
Verhoeff NP, Wilson AA, Takeshita S, Trop L, Hussey
D, Singh K, Kung HF, Kung MP, Houle S (2004) Invivo imaging of Alzheimer disease beta-amyloid with
[11C]SB-13 PET. Am J Geriatr Psychiatry 12, 584-595.
Zha Z, Choi SR, Ploessl K, Lieberman BP, Qu W, Hefti F,
Mintun M, Skovronsky D, Kung HF (2011) Multidentate
(18)F-polypegylated styrylpyridines as imaging agents for
Abeta plaques in cerebral amyloid angiopathy (CAA). J
Med Chem 54, 8085-8098.
Petric A, Johnson SA, Pham HV, Li Y, Ceh S, Golobic A,
Agdeppa ED, Timbol G, Liu J, Keum G, Satyamurthy N,
Kepe V, Houk KN, Barrio JR (2012) Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of
electronic structures and geometries to binding affinities.
Proc Natl Acad Sci U S A 109, 16492-16497.
Cui M, Ono M, Kimura H, Ueda M, Nakamoto Y, Togashi
K, Okamoto Y, Ihara M, Takahashi R, Liu B, Saji H (2012)
Novel (18)F-labeled benzoxazole derivatives as potential
positron emission tomography probes for imaging of cerebral beta-amyloid plaques in Alzheimer’s disease. J Med
Chem 55, 9136-9145.
Cui M, Wang X, Yu P, Zhang J, Li Z, Zhang X, Yang
Y, Ono M, Jia H, Saji H, Liu B (2012) Synthesis and
evaluation of novel (18)F labeled 2-pyridinylbenzoxazole
and 2-pyridinylbenzothiazole derivatives as ligands for
positron emission tomography (PET) imaging of betaamyloid plaques. J Med Chem 55, 9283-9296.
Johnson AE, Jeppsson F, Sandell J, Wensbo D, Neelissen
JA, Jureus A, Strom P, Norman H, Farde L, Svensson SP
(2009) AZD2184: A radioligand for sensitive detection of
beta-amyloid deposits. J Neurochem 108, 1177-1186.
Nyberg S, Jonhagen ME, Cselenyi Z, Halldin C, Julin
P, Olsson H, Freund-Levi Y, Andersson J, Varnas K,
Svensson S, Farde L (2009) Detection of amyloid in
Alzheimer’s disease with positron emission tomography
using [11C]AZD2184. Eur J Nucl Med Mol Imaging 36,
1859-1863.
Andersson JD, Varnas K, Cselenyi Z, Gulyas B, Wensbo
D, Finnema SJ, Swahn BM, Svensson S, Nyberg S,
Farde L, Halldin C (2010) Radiosynthesis of the candidate beta-amyloid radioligand [(11)C]AZD2184: Positron
emission tomography examination and metabolite analysis
in cynomolgus monkeys. Synapse 64, 733-741.
Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli
LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang
SC, Barrio JR (2002) Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living
patients with Alzheimer disease. Am J Geriatr Psychiatry
10, 24-35.
Ossenkoppele R, Tolboom N, Foster-Dingley JC, Adriaanse SF, Boellaard R, Yaqub M, Windhorst AD,
Barkhof F, Lammertsma AA, Scheltens P, van der Flier
WM, van Berckel BN (2012) Longitudinal imaging of
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1240]
[1241]
[1242]
[1243]
[1244]
[1245]
[1246]
[1247]
[1248]
[1249]
[1250]
[1251]
Alzheimer pathology using [(11)C]PIB, [(18)F]FDDNP
and [(18)F]FDG PET. Eur J Nucl Med Mol Imaging 39,
990-1000.
Protas HD, Kepe V, Hayashi KM, Klunder AD, Braskie
MN, Ercoli L, Siddarth P, Bookheimer SY, Thompson PM,
Small GW, Barrio JR, Huang SC (2012) Prediction of cognitive decline based on hemispheric cortical surface maps
of FDDNP PET. Neuroimage 61, 749-760.
Cai L, Cuevas J, Temme S, Herman MM, Dagostin C,
Widdowson DA, Innis RB, Pike VW (2007) Synthesis
and structure-affinity relationships of new 4-(6-iodoH-imidazo[1,2-a]pyridin-2-yl)-N-dimethylbenzeneamine
derivatives as ligands for human beta-amyloid plaques. J
Med Chem 50, 4746-4758.
Ryu EK, Chen X (2008) Development of Alzheimer’s disease imaging agents for clinical studies. Front Biosci 13,
777-789.
Zhuang ZP, Kung MP, Wilson A, Lee CW, Plossl K,
Hou C, Holtzman DM, Kung HF (2003) Structure-activity
relationship of imidazo[1,2-a]pyridines as ligands for
detecting beta-amyloid plaques in the brain. J Med Chem
46, 237-243.
Newberg AB, Wintering NA, Plossl K, Hochold J, Stabin
MG, Watson M, Skovronsky D, Clark CM, Kung MP,
Kung HF (2006) Safety, biodistribution, and dosimetry of
123I-IMPY: A novel amyloid plaque-imaging agent for the
diagnosis of Alzheimer’s disease. J Nucl Med 47, 748-754.
Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfai T, Alanine A,
Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD,
Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray
S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins
PN (2002) Targeted pharmacological depletion of serum
amyloid P component for treatment of human amyloidosis.
Nature 417, 254-259.
Kolstoe SE, Wood SP (2010) Drug targets for amyloidosis.
Biochem Soc Trans 38, 466-470.
Millar DJ, Hutchinson WL, Pepys MB (2011) Immunoradiometric assay for human serum amyloid P component.
J Immunol Methods 371, 18-24.
Kolstoe SE, Ridha BH, Bellotti V, Wang N, Robinson
CV, Crutch SJ, Keir G, Kukkastenvehmas R, Gallimore
JR, Hutchinson WL, Hawkins PN, Wood SP, Rossor MN,
Pepys MB (2009) Molecular dissection of Alzheimer’s
disease neuropathology by depletion of serum amyloid P
component. Proc Natl Acad Sci U S A 106, 7619-7623.
Bodin K, Ellmerich S, Kahan MC, Tennent GA, Loesch
A, Gilbertson JA, Hutchinson WL, Mangione PP, Gallimore JR, Millar DJ, Minogue S, Dhillon AP, Taylor GW,
Bradwell AR, Petrie A, Gillmore JD, Bellotti V, Botto
M, Hawkins PN, Pepys MB (2010) Antibodies to human
serum amyloid P component eliminate visceral amyloid
deposits. Nature 468, 93-97.
Gillmore JD, Tennent GA, Hutchinson WL, Gallimore
JR, Lachmann HJ, Goodman HJ, Offer M, Millar DJ,
Petrie A, Hawkins PN, Pepys MB (2010) Sustained
pharmacological depletion of serum amyloid P component
in patients with systemic amyloidosis. Br J Haematol 148,
760-767.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H,
Guido T, Hu K, Huang J, Johnson-Wood K, Khan K,
Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R,
Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert
C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates
[1252]
[1253]
[1254]
[1255]
[1256]
[1257]
[1258]
[1259]
[1260]
[1261]
[1262]
[1263]
[1264]
[1265]
[1266]
[1267]
97
Alzheimer-disease-like pathology in the PDAPP mouse.
Nature 400, 173-177.
Schenk D (2002) Amyloid-beta immunotherapy for
Alzheimer’s disease: The end of the beginning. Nat Rev
Neurosci 3, 824-828.
Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel
M, Kirby LC, Jouanny P, Dubois B, Eisner L, Flitman S,
Michel BF, Boada M, Frank A, Hock C (2003) Subacute
meningoencephalitis in a subset of patients with AD after
Abeta42 immunization. Neurology 61, 46-54.
Hock C, Konietzko U, Papassotiropoulos A, Wollmer A,
Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM
(2002) Generation of antibodies specific for beta-amyloid
by vaccination of patients with Alzheimer disease. Nat
Med 8, 1270-1275.
Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A,
Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia
E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann
M, Maddalena A, Papassotiropoulos A, Nitsch RM (2003)
Antibodies against beta-amyloid slow cognitive decline in
Alzheimer’s disease. Neuron 38, 547-554.
Imbimbo BP (2002) Toxicity of beta-amyloid vaccination
in patients with Alzheimer’s disease. Ann Neurol 51, 794.
Imbimbo BP (2002) ␤-Amyloid immunization approaches
for Alzheimer’s disease. Drug Dev Res 56, 150-162.
Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H,
Weller RO (2003) Neuropathology of human Alzheimer
disease after immunization with amyloid-beta peptide: A
case report. Nat Med 9, 448-452.
Nicoll JA, Barton E, Boche D, Neal JW, Ferrer I, Thompson P, Vlachouli C, Wilkinson D, Bayer A, Games D,
Seubert P, Schenk D, Holmes C (2006) Abeta species
removal after abeta42 immunization. J Neuropathol Exp
Neurol 65, 1040-1048.
Robinson SR, Bishop GM, Lee HG, Munch G (2004)
Lessons from the AN 1792 Alzheimer vaccine: Lest we
forget. Neurobiol Aging 25, 609-615.
Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson
KR, Jenkins L, Millais SB, Donoghue S (2005) Evaluation
of the safety and immunogenicity of synthetic Abeta42
(AN1792) in patients with AD. Neurology 64, 94-101.
Boche D, Nicoll JA, Weller RO (2005) Immunotherapy
for Alzheimer’s disease and other dementias. Curr Opin
Neurol 18, 720-725.
Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA (2008)
Consequence of Abeta immunization on the vasculature of
human Alzheimer’s disease brain. Brain 131, 3299-3310.
Boche D, Donald J, Love S, Harris S, Neal JW, Holmes
C, Nicoll JA (2010) Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42
immunisation in Alzheimer’s disease. Acta Neuropathol
120, 13-20.
Boche D, Denham N, Holmes C, Nicoll JA (2010)
Neuropathology after active Abeta42 immunotherapy:
Implications for Alzheimer’s disease pathogenesis. Acta
Neuropathol 120, 369-384.
Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox
NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM
(2005) Clinical effects of Abeta immunization (AN1792)
in patients with AD in an interrupted trial. Neurology 64,
1553-1562.
Hock C, Nitsch RM (2005) Clinical observations with AN1792 using TAPIR analyses. Neurodegener Dis 2, 273276.
98
[1268]
[1269]
[1270]
[1271]
[1272]
[1273]
[1274]
[1275]
[1276]
[1277]
[1278]
[1279]
[1280]
[1281]
[1282]
[1283]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Lee M, Bard F, Johnson-Wood K, Lee C, Hu K, Griffith SG,
Black RS, Schenk D, Seubert P (2005) Abeta42 immunization in Alzheimer’s disease generates Abeta N-terminal
antibodies. Ann Neurol 58, 430-435.
Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C,
Seubert P, Games D, Kirby L, Schenk D (2005) Abeta
vaccination effects on plaque pathology in the absence
of encephalitis in Alzheimer disease. Neurology 64,
129-131.
O’Toole M, Janszen DB, Slonim DK, Reddy PS, Ellis DK,
Legault HM, Hill AA, Whitley MZ, Mounts WM, Zuberek
K, Immermann FW, Black RS, Dorner AJ (2005) Risk factors associated with beta-amyloid(1-42) immunotherapy in
preimmunization gene expression patterns of blood cells.
Arch Neurol 62, 1531-1536.
Schenk DB, Seubert P, Grundman M, Black R (2005)
A beta immunotherapy: Lessons learned for potential
treatment of Alzheimer’s disease. Neurodegener Dis 2,
255-260.
Patton RL, Kalback WM, Esh CL, Kokjohn TA, Van Vickle
GD, Luehrs DC, Kuo YM, Lopez J, Brune D, Ferrer I,
Masliah E, Newel AJ, Beach TG, Castano EM, Roher
AE (2006) Amyloid-beta peptide remnants in AN-1792immunized Alzheimer’s disease patients: A biochemical
analysis. Am J Pathol 169, 1048-1063.
Vasilevko V, Cribbs DH (2006) Novel approaches for
immunotherapeutic intervention in Alzheimer’s disease.
Neurochem Int 49, 113-126.
Bombois S, Maurage CA, Gompel M, Deramecourt V,
kowiak-Cordoliani MA, Black RS, Lavielle R, Delacourte
A, Pasquier F (2007) Absence of beta-amyloid deposits
after immunization in Alzheimer disease with Lewy body
dementia. Arch Neurol 64, 583-587.
Koepsell TD, Chi YY, Zhou XH, Lee WW, Ramos EM,
Kukull WA (2007) An alternative method for estimating
efficacy of the AN1792 vaccine for Alzheimer disease.
Neurology 69, 1868-1872.
Hawkes CA, McLaurin J (2008) Clinical immunotherapy
trials in Alzheimer’s disease. Drug Discovery Today: Therapeutic Strategies 5, 177-183.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins
V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova
E, Nicoll JA (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised,
placebo-controlled phase I trial. Lancet 372, 216-223.
Holtzman DM (2008) Alzheimer’s disease: Moving
towards a vaccine. Nature 454, 418-420.
Pride M, Seubert P, Grundman M, Hagen M, Eldridge J,
Black RS (2008) Progress in the active immunotherapeutic
approach to Alzheimer’s disease: Clinical investigations
into AN1792-associated meningoencephalitis. Neurodegener Dis 5, 194-196.
St George-Hyslop PH, Morris JC (2008) Will anti-amyloid
therapies work for Alzheimer’s disease? Lancet 372, 180182.
Kokjohn TA, Roher AE (2009) Antibody responses,
amyloid-beta peptide remnants and clinical effects of AN1792 immunization in patients with AD in an interrupted
trial. CNS Neurol Disord Drug Targets 8, 88-97.
Town T (2009) Alternative Abeta immunotherapy
approaches for Alzheimer’s disease. CNS Neurol Disord
Drug Targets 8, 114-127.
Vellas B, Black R, Thal LJ, Fox NC, Daniels M, McLennan G, Tompkins C, Leibman C, Pomfret M, Grundman M
(2009) Long-term follow-up of patients immunized with
[1284]
[1285]
[1286]
[1287]
[1288]
[1289]
[1290]
[1291]
[1292]
[1293]
[1294]
[1295]
[1296]
[1297]
AN1792: Reduced functional decline in antibody responders. Curr Alzheimer Res 6, 144-151.
Serrano-Pozo A, William CM, Ferrer I, Uro-Coste E,
Delisle MB, Maurage CA, Hock C, Nitsch RM, Masliah
E, Growdon JH, Frosch MP, Hyman BT (2010) Beneficial
effect of human anti-amyloid-beta active immunization on
neurite morphology and tau pathology. Brain 133, 13121327.
Uro-Coste E, Russano de PG, Guilbeau-Frugier C, Sastre
N, Ousset PJ, da Silva NA, Lavialle-Guillotreau V, Vellas
B, Delisle MB (2010) Cerebral amyloid angiopathy and
microhemorrhages after amyloid beta vaccination: Case
report and brief review. Clin Neuropathol 29, 209-216.
Zotova E, Holmes C, Johnston D, Neal JW, Nicoll
JA, Boche D (2011) Microglial alterations in human
Alzheimer’s disease following Abeta42 immunization.
Neuropathol Appl Neurobiol 37, 513-524.
Schneeberger A, Mandler M, Otawa O, Zauner W, Mattner F, Schmidt W (2009) Development of AFFITOPE
vaccines for Alzheimer’s disease (AD)–from concept to
clinical testing. J Nutr Health Aging 13, 264-267.
Schneeberger A, Mandler M, Mattner F, Schmidt W
(2010) AFFITOME(R) technology in neurodegenerative
diseases: The doubling advantage. Hum Vaccin 6, 948-952.
Winblad B, Andreasen N, Minthon L, Floesser A,
Imbert G, Dumortier T, Maguire RP, Blennow K,
Lundmark J, Staufenbiel M, Orgogozo JM, Graf A
(2012) Safety, tolerability, and antibody response of
active Abeta immunotherapy with CAD106 in patients
with Alzheimer’s disease: Randomised, double-blind,
placebo-controlled, first-in-human study. Lancet Neurol
11, 597-604.
Wisniewski T (2012) Active immunotherapy for
Alzheimer’s disease. Lancet Neurol 11, 571-572.
Kingwell K (2012) Alzheimer disease: Amyloid-beta
immunotherapy CAD106 passes first safety test in patients
with Alzheimer disease. Nat Rev Neurol 8, 414.
Dyer MR, Renner WA, Bachmann MF (2006) A second
vaccine revolution for the new epidemics of the 21st century. Drug Discov Today 11, 1028-1033.
Jennings GT, Bachmann MF (2008) The coming of age of
virus-like particle vaccines. Biol Chem 389, 521-536.
Wiessner C, Wiederhold KH, Tissot AC, Frey P, Danner S,
Jacobson LH, Jennings GT, Luond R, Ortmann R, Reichwald J, Zurini M, Mir A, Bachmann MF, Staufenbiel M
(2011) The second-generation active Abeta immunotherapy CAD106 reduces amyloid accumulation in APP
transgenic mice while minimizing potential side effects.
J Neurosci 31, 9323-9331.
Ryan JM, Grundman M (2009) Anti-amyloid-beta
immunotherapy in Alzheimer’s disease: ACC-001 clinical
trials are ongoing. J Alzheimers Dis 17, 243.
Muhs A, Hickman DT, Pihlgren M, Chuard N, Giriens
V, Meerschman C, Van der Auwera I, Van Leuven F,
Sugawara M, Weingertner MC, Bechinger B, Greferath
R, Kolonko N, Nagel-Steger L, Riesner D, Brady RO,
Pfeifer A, Nicolau C (2007) Liposomal vaccines with
conformation-specific amyloid peptide antigens define
immune response and efficacy in APP transgenic mice.
Proc Natl Acad Sci U S A 104, 9810-9815.
Hickman DT, Lopez-Deber MP, Ndao DM, Silva AB,
Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A,
Karastaneva H, Nagel-Steger L, Willbold D, Riesner D,
Nicolau C, Baldus M, Pfeifer A, Muhs A (2011) Sequenceindependent control of peptide conformation in liposomal
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1298]
[1299]
[1300]
[1301]
[1302]
[1303]
[1304]
[1305]
[1306]
[1307]
[1308]
[1309]
vaccines for targeting protein misfolding diseases. J Biol
Chem 286, 13966-13976.
Wang CY, Finstad CL, Walfield AM, Sia C, Sokoll KK,
Chang TY, Fang XD, Hung CH, Hutter-Paier B, Windisch
M (2007) Site-specific UBITh amyloid-beta vaccine for
immunotherapy of Alzheimer’s disease. Vaccine 25, 30413052.
Savage MJ, Wu G, McCampbell A, Wessner KR, Citron M, Liang X, Hsieh S, Wolfe AL, Kinney GG, Rosen
LB, Renger JJ (2010) A novel multivariant Abetapeptide
vaccine with preclinical evidence of a central immune
response that generates antisera recognizing a wide range
of Abeta peptide species. Alzheimers Dement 6, S142.
Davtyan H, Ghochikyan A, Movsesyan N, Ellefsen B,
Petrushina I, Cribbs DH, Hannaman D, Evans CF, Agadjanyan MG (2012) Delivery of a DNA vaccine for
Alzheimer’s disease by electroporation versus gene gun
generates potent and similar immune responses. Neurodegener Dis 10, 261-264.
Xing XN, Zhang WG, Sha S, Li Y, Guo R, Wang C,
Cao YP (2011) Amyloid beta 3-10 DNA vaccination suggests a potential new treatment for Alzheimer’s disease in
BALB/c mice. Chin Med J (Engl) 124, 2636-2641.
Xing X, Sha S, Li Y, Zong L, Jiang T, Cao Y (2012) Immunization with a new DNA vaccine for Alzheimer’s disease
elicited Th2 immune response in BALB/c mice by in vivo
electroporation. J Neurol Sci 313, 17-21.
Ma Y, Li Y, Zong LX, Xing XN, Zhang WG, Cao
YP (2011) Improving memory and decreasing cognitive
impairment in Tg-APPswe/PSEN1dE9 mice with Abeta310 repeat fragment plasmid by reducing Abeta deposition
and inflammatory response. Brain Res 1400, 112-124.
Li Y, Ma Y, Zong LX, Xing XN, Sha S, Cao YP (2011)
Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Abeta3-10 induces Th2 immune response
against amyloid-beta in wild-type mouse. Neurosci Lett
505, 128-133.
Li Y, Ma Y, Zong LX, Xing XN, Guo R, Jiang TZ, Sha S,
Liu L, Cao YP (2012) Intranasal inoculation with an adenovirus vaccine encoding ten repeats of Abeta3-10 reduces
AD-like pathology and cognitive impairment in TgAPPswe/PSEN1dE9 mice. J Neuroimmunol 249, 16-26.
Santuccione AC, Merlini M, Shetty A, Tackenberg C, Bali
J, Ferretti MT, McAfoose J, Kulic L, Bernreuther C, Welt
T, Grimm J, Glatzel M, Rajendran L, Hock C, Nitsch
RM (2012) Active vaccination with ankyrin G reduces
beta-amyloid pathology in APP transgenic mice. Mol
Psychiatry, doi: 10.1038/mp.2012.70 [Epub ahead of
print].
Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E,
Landa G, Cohen H, Schwartz M (2006) Glatiramer acetate
fights against Alzheimer’s disease by inducing dendriticlike microglia expressing insulin-like growth factor 1. Proc
Natl Acad Sci U S A 103, 11784-11789.
Hara H, Inoue M, Adachi K, Yonemitsu Y, Hasegawa M,
Nabeshima T, Tabira T (2007) [Mucosal immunotherapy
for alzheimer’s disease with viral vectors]. Nihon Shinkei
Seishin Yakurigaku Zasshi 27, 53-56.
Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y,
Schmidt SD, Chishti MA, Horne P, Heslin D, French J,
Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser
PE, St George-Hyslop P, Westaway D (2000) A beta peptide immunization reduces behavioural impairment and
plaques in a model of Alzheimer’s disease. Nature 408,
979-982.
[1310]
[1311]
[1312]
[1313]
[1314]
[1315]
[1316]
[1317]
[1318]
[1319]
[1320]
[1321]
[1322]
99
Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey
C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D,
Connor K, Hatcher J, Hope C, Gordon M, Arendash GW
(2000) A beta peptide vaccination prevents memory loss
in an animal model of Alzheimer’s disease. Nature 408,
982-985.
Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T (2001) Immunization with a
nontoxic/nonfibrillar amyloid-beta homologous peptide
reduces Alzheimer’s disease-associated pathology in
transgenic mice. Am J Pathol 159, 439-447.
Qu B, Rosenberg RN, Li L, Boyer PJ, Johnston SA (2004)
Gene vaccination to bias the immune response to amyloidbeta peptide as therapy for Alzheimer disease. Arch Neurol
61, 1859-1864.
Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko
V, Movsesyan N, Mkrtichyan M, Saing T, Cribbs DH
(2005) Prototype Alzheimer’s disease vaccine using the
immunodominant B cell epitope from beta-amyloid and
promiscuous T cell epitope pan HLA DR-binding peptide.
J Immunol 174, 1580-1586.
Asuni AA, Boutajangout A, Scholtzova H, Knudsen E, Li
YS, Quartermain D, Frangione B, Wisniewski T, Sigurdsson EM (2006) Vaccination of Alzheimer’s model mice
with Abeta derivative in alum adjuvant reduces Abeta
burden without microhemorrhages. Eur J Neurosci 24,
2530-2542.
Lemere CA, Maier M, Jiang L, Peng Y, Seabrook TJ (2006)
Amyloid-beta immunotherapy for the prevention and treatment of Alzheimer disease: Lessons from mice, monkeys,
and humans. Rejuvenation Res 9, 77-84.
Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C,
Lemere CA (2006) Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in
an Alzheimer’s disease mouse model in the absence of an
Abeta-specific cellular immune response. J Neurosci 26,
4717-4728.
Seabrook TJ, Jiang L, Thomas K, Lemere CA (2006)
Boosting with intranasal dendrimeric Abeta1-15 but not
Abeta1-15 peptide leads to an effective immune response
following a single injection of Abeta1-40/42 in APP-tg
mice. J Neuroinflammation 3, 14.
Seabrook TJ, Thomas K, Jiang L, Bloom J, Spooner
E, Maier M, Bitan G, Lemere CA (2007) Dendrimeric
Abeta1-15 is an effective immunogen in wildtype and
APP-tg mice. Neurobiol Aging 28, 813-823.
Lemere CA, Maier M, Peng Y, Jiang L, Seabrook TJ
(2007) Novel Abeta immunogens: Is shorter better? Curr
Alzheimer Res 4, 427-436.
Mouri A, Noda Y, Hara H, Mizoguchi H, Tabira T,
Nabeshima T (2007) Oral vaccination with a viral vector containing Abeta cDNA attenuates age-related Abeta
accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. FASEB J 21,
2135-2148.
Nikolic WV, Bai Y, Obregon D, Hou H, Mori T, Zeng
J, Ehrhart J, Shytle RD, Giunta B, Morgan D, Town T,
Tan J (2007) Transcutaneous beta-amyloid immunization
reduces cerebral beta-amyloid deposits without T cell infiltration and microhemorrhage. Proc Natl Acad Sci U S A
104, 2507-2512.
Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan
G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH,
Agadjanyan MG (2007) Alzheimer’s disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric
100
[1323]
[1324]
[1325]
[1326]
[1327]
[1328]
[1329]
[1330]
[1331]
[1332]
[1333]
[1334]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Abeta species in amyloid precursor protein transgenic
mice. J Neurosci 27, 12721-12731.
Petrushina I, Ghochikyan A, Mkrtichyan M, Mamikonyan
G, Movsesyan N, Ajdari R, Vasilevko V, Karapetyan A,
Lees A, Agadjanyan MG, Cribbs DH. (2008) MannanAbeta28 conjugate prevents Abeta-plaque deposition, but
increases microhemorrhages in the brains of vaccinated
Tg2576 (APPsw) mice. J Neuroinflammation 5, 42
Movsesyan N, Mkrtichyan M, Petrushina I, Ross TM,
Cribbs DH, Agadjanyan MG, Ghochikyan A (2008)
DNA epitope vaccine containing complement component
C3d enhances anti-amyloid-beta antibody production and
polarizes the immune response towards a Th2 phenotype.
J Neuroimmunol 205, 57-63.
Boutajangout A, Goni F, Knudsen E, Schreiber F, Asuni A,
Quartermain D, Frangione B, Chabalgoity A, Wisniewski
T, Sigurdsson EM (2009) Diminished amyloid-beta burden
in Tg2576 mice following a prophylactic oral immunization with a salmonella-based amyloid-beta derivative
vaccine. J Alzheimers Dis 18, 961-972.
Kitazawa M, Vasilevko V, Cribbs DH, LaFerla FM (2009)
Immunization with amyloid-beta attenuates inclusion
body myositis-like myopathology and motor impairment
in a transgenic mouse model. J Neurosci 29, 61326141.
Trouche SG, Asuni A, Rouland S, Wisniewski T, Frangione B, Verdier JM, Sigurdsson EM, Mestre-Frances N
(2009) Antibody response and plasma Abeta1-40 levels
in young Microcebus murinus primates immunized with
Abeta1-42 and its derivatives. Vaccine 27, 957-964.
Wilcock DM, Gharkholonarehe N, Van Nostrand WE,
Davis J, Vitek MP, Colton CA (2009) Amyloid reduction by amyloid-beta vaccination also reduces mouse tau
pathology and protects from neuron loss in two mouse
models of Alzheimer’s disease. J Neurosci 29, 79577965.
Ishii-Katsuno R, Nakajima A, Katsuno T, Nojima J,
Futai E, Sasagawa N, Yoshida T, Watanabe Y, Ishiura S
(2010) Reduction of amyloid beta-peptide accumulation
in Tg2576 transgenic mice by oral vaccination. Biochem
Biophys Res Commun 399, 593-599.
Vasilevko V, Pop V, Kim HJ, Saing T, Glabe CC, Milton S,
Barrett EG, Cotman CW, Cribbs DH, Head E (2010) Linear
and conformation specific antibodies in aged beagles after
prolonged vaccination with aggregated Abeta. Neurobiol
Dis 39, 301-310.
Vollmar P, Kullmann JS, Thilo B, Claussen MC, Rothhammer V, Jacobi H, Sellner J, Nessler S, Korn T, Hemmer
B (2010) Active immunization with amyloid-beta 1-42
impairs memory performance through TLR2/4-dependent
activation of the innate immune system. J Immunol 185,
6338-6347.
Wang CM, deVries S, Camboni M, Glass M, Martin PT
(2010) Immunization with the SDPM1 peptide lowers
amyloid plaque burden and improves cognitive function
in the APPswePSEN1(A246E) transgenic mouse model
of Alzheimer’s disease. Neurobiol Dis 39, 409-422.
Mantile F, Basile C, Cicatiello V, De FD, Caivano A, De
BP, Prisco A (2011) A multimeric immunogen for the
induction of immune memory to beta-amyloid. Immunol
Cell Biol 89, 604-609.
Axelsen TV, Holm A, Christiansen G, Birkelund S (2011)
Identification of the shortest Abeta-peptide generating
highly specific antibodies against the C-terminal end of
amyloid-beta42. Vaccine 29, 3260-3269.
[1335]
[1336]
[1337]
[1338]
[1339]
[1340]
[1341]
[1342]
[1343]
[1344]
[1345]
[1346]
[1347]
[1348]
[1349]
[1350]
[1351]
[1352]
[1353]
[1354]
[1355]
[1356]
Kofler J, Lopresti B, Janssen C, Trichel AM, Masliah E,
Finn OJ, Salter RD, Murdoch GH, Mathis CA, Wiley CA
(2012) Preventive immunization of aged and juvenile nonhuman primates to beta-amyloid. J Neuroinflammation 9,
84.
Esiri MM (2001) Is an effective immune intervention for
Alzheimer’s disease in prospect? Trends Pharmacol Sci
22, 2-3.
Ingram DK (2001) Vaccine development for Alzheimer’s
disease: A shot of good news. Trends Neurosci 24, 305307.
Sigurdsson EM, Wisniewski T, Frangione B (2002) A
safer vaccine for Alzheimer’s disease? Neurobiol Aging
23, 1001-1008.
Sigurdsson EM, Frangione B, Wisniewski T (2002) Immunization for Alzheimer’s disease. Drug Develop Res 56,
135-142.
Solomon B (2002) Towards Alzheimer’s disease vaccination. Mini Rev Med Chem 2, 85-92.
Wisniewski T, Sigurdsson EM (2002) Immunization treatment approaches in Alzheimer’s and prion diseases. Curr
Neurol Neurosci Rep 2, 400-404.
Dodart JC, Bales KR, Paul SM (2003) Immunotherapy for
Alzheimer’s disease: Will vaccination work? Trends Mol
Med 9, 85-87.
Broytman O, Malter JS (2004) Anti-Abeta: The good, the
bad, and the unforeseen. J Neurosci Res 75, 301-306.
Brown ME, Dasilva KA, McLaurin J (2005) Refining an
Alzheimer’s vaccine to avoid an inflammatory response.
Expert Opin Biol Ther 5, 809-816.
Goni F, Sigurdsson EM (2005) New directions towards
safer and effective vaccines for Alzheimer’s disease. Curr
Opin Mol Ther 7, 17-23.
Rosenberg RN (2005) Immunotherapy for Alzheimer disease: The promise and the problem. Arch Neurol 62,
1506-1507.
Dasilva KA, Aubert I, McLaurin J (2006) Vaccine development for Alzheimer’s disease. Curr Pharm Des 12,
4283-4293.
Sigurdsson EM (2006) Immunotherapy for conformational
diseases. Curr Pharm Des 12, 2569-2585.
Solomon B (2006) Alzheimer’s disease immunotherapy:
From in vitro amyloid immunomodulation to in vivo vaccination. J Alzheimers Dis 9, 433-438.
Weiner HL, Frenkel D (2006) Immunology and
immunotherapy of Alzheimer’s disease. Nat Rev Immunol
6, 404-416.
Mohajeri MH (2007) The underestimated potential of
the immune system in prevention of Alzheimer’s disease
pathology. Bioessays 29, 927-932.
Purcell AW, McCluskey J, Rossjohn J (2007) More than
one reason to rethink the use of peptides in vaccine design.
Nat Rev Drug Discov 6, 404-414.
Solomon B (2007) Beta-amyloidbased immunotherapy as
a treatment of Alzheimers disease. Drugs Today (Barc) 43,
333-342.
Solomon B (2007) Clinical immunologic approaches for
the treatment of Alzheimer’s disease. Expert Opin Investig
Drugs 16, 819-828.
Solomon B (2007) Active immunization against
Alzheimer’s beta-amyloid peptide using phage display
technology. Vaccine 25, 3053-3056.
Brody DL, Holtzman DM (2008) Active and passive
immunotherapy for neurodegenerative disorders. Annu
Rev Neurosci 31, 175-193.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1357]
[1358]
[1359]
[1360]
[1361]
[1362]
[1363]
[1364]
[1365]
[1366]
[1367]
[1368]
[1369]
[1370]
[1371]
[1372]
[1373]
[1374]
[1375]
[1376]
[1377]
Nitsch RM, Hock C (2008) Targeting beta-amyloid pathology in Alzheimer’s disease with Abeta immunotherapy.
Neurotherapeutics 5, 415-420.
Popovich PG, Longbrake EE (2008) Can the immune system be harnessed to repair the CNS? Nat Rev Neurosci 9,
481-493.
Solomon B (2008) Immunological approaches for
amyloid-beta clearance toward treatment for Alzheimer’s
disease. Rejuvenation Res 11, 349-357.
Agadjanyan MG, Cribbs DH (2009) Active and passive
Abeta-immunotherapy: Preclinical and clinical studies and
future directions: Part I. CNS Neurol Disord Drug Targets
8, 1-6.
Cribbs DH, Agadjanyan MG (2009) Active and passive
Abeta-immunotherapy: Preclinical and clinical studies and
future directions: Part II. CNS Neurol Disord Drug Targets
8, 82-87.
Foster JK, Verdile G, Bates KA, Martins RN (2009) Immunization in Alzheimer’s disease: Naive hope or realistic
clinical potential? Mol Psychiatry 14, 239-251.
Solomon B (2009) Immunotherapeutic strategies for
Alzheimer’s disease treatment. ScientificWorldJournal 9,
909-919.
Cribbs DH (2010) Abeta DNA vaccination for Alzheimer’s
disease: Focus on disease prevention. CNS Neurol Disord
Drug Targets 9, 207-216.
Lemere CA, Masliah E (2010) Can Alzheimer disease
be prevented by amyloid-beta immunotherapy? Nat Rev
Neurol 6, 108-119.
Maarouf CL, Daugs ID, Kokjohn TA, Kalback WM, Patton
RL, Luehrs DC, Masliah E, Nicoll JA, Sabbagh MN, Beach
TG, Castano EM, Roher AE (2010) The biochemical aftermath of anti-amyloid immunotherapy. Mol Neurodegener
5, 39.
Solomon B, Frenkel D (2010) Immunotherapy for
Alzheimer’s disease. Neuropharmacology 59, 303-309.
von Bernhardi R (2010) Immunotherapy in Alzheimer’s
disease: Where do we stand? Where should we go? J
Alzheimers Dis 19, 405-421.
Wang YJ, Zhou HD, Zhou XF (2010) Modified
immunotherapies against Alzheimer’s disease: Toward
safer and effective amyloid clearance. J Alzheimers Dis
21, 1065-1075.
Wisniewski T, Boutajangout A (2010) Vaccination as a
therapeutic approach to Alzheimer’s disease. Mt Sinai J
Med 77, 17-31.
Menendez-Gonzalez M, Perez-Pinera P, Martinez-Rivera
M, Muniz AL, Vega JA (2011) Immunotherapy for
Alzheimer’s disease: Rational basis in ongoing clinical
trials. Curr Pharm Des 17, 508-520.
Morgan D (2011) Immunotherapy for Alzheimer’s disease.
J Internal Med 269, 54-63.
Schnabel J (2011) Vaccines: Chasing the dream. Nature
475, S18-S19.
Shah S, Federoff HJ (2011) Therapeutic potential of vaccines for Alzheimer’s disease. Immunotherapy 3, 287-298.
Delrieu J, Ousset PJ, Caillaud C, Vellas B (2012)
‘Clinical trials in Alzheimer’s disease’: Immunotherapy
approaches. J Neurochem 120(Suppl 1), 186-193.
Lobello K, Ryan JM, Liu E, Rippon G, Black R
(2012) Targeting Beta amyloid: A clinical review of
immunotherapeutic approaches in Alzheimer’s disease. Int
J Alzheimers Dis 2012, 628070.
Bach P, Tschape JA, Kopietz F, Braun G, Baade JK,
Wiederhold KH, Staufenbiel M, Prinz M, Deller T, Kalinke
[1378]
[1379]
[1380]
[1381]
[1382]
[1383]
[1384]
[1385]
[1386]
[1387]
[1388]
[1389]
[1390]
101
U, Buchholz CJ, Muller UC (2009) Vaccination with
Abeta-displaying virus-like particles reduces soluble and
insoluble cerebral Abeta and lowers plaque burden in APP
transgenic mice. J Immunol 182, 7613-7624.
Zurbriggen R, Amacker M, Kammer AR, Westerfeld N,
Borghgraef P, Van LF, Van dA I, Wera S (2005) Virosomebased active immunization targets soluble amyloid species
rather than plaques in a transgenic mouse model of
Alzheimer’s disease. J Mol Neurosci 27, 157-166.
Salloway S, Sperling R, Gilman S, Fox NC, Blennow
K, Raskind M, Sabbagh M, Honig LS, Doody R, van
Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E,
Lieberburg I, Schenk D, Black R, Grundman M (2009) A
phase 2 multiple ascending dose trial of bapineuzumab in
mild to moderate Alzheimer disease. Neurology 73, 20612070.
Black RS, Sperling RA, Safirstein B, Motter RN, Pallay
A, Nichols A, Grundman M (2010) A single ascending
dose study of bapineuzumab in patients with Alzheimer
disease. Alzheimer Dis Assoc Disord 24, 198-203.
Laskowitz DT, Kolls BJ (2010) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate
Alzheimer disease. Neurology 74, 2026-2027.
Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J,
Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson
AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E,
Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M (2012) Amyloid-related imaging abnormalities
in patients with Alzheimer’s disease treated with bapineuzumab: A retrospective analysis. Lancet Neurol 11,
241-249.
Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R,
Klunk WE, Mathis CA, Blennow K, Barakos J, Okello
AA, Rodriguez Martinez de LS, Liu E, Koller M, Gregg
KM, Schenk D, Black R, Grundman M (2010) 11C-PiB
PET assessment of change in fibrillar amyloid-beta load
in patients with Alzheimer’s disease treated with bapineuzumab: A phase 2, double-blind, placebo-controlled,
ascending-dose study. Lancet Neurol 9, 363-372.
Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei
J, Black R, Grundman M, Liu E (2012) Effect of
immunotherapy with bapineuzumab on cerebrospinal fluid
biomarker levels in patients with mild to moderate
Alzheimer disease. Arch Neurol 69, 1002-1010.
Kerchner GA, Boxer AL (2010) Bapineuzumab. Expert
Opin Biol Ther 10, 1121-1130.
Wilcock GK (2010) Bapineuzumab in Alzheimer’s disease: Where now? Lancet Neurol 9, 134-136.
Panza F, Frisardi V, Imbimbo BP, D’Onofrio G, Pietrarossa
G, Seripa D, Pilotto A, Solfrizzi V (2010) Bapineuzumab:
Anti-beta-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. Immunotherapy 2, 767-782.
Panza F, Frisardi V, Imbimbo BP, Seripa D, Solfrizzi
V, Pilotto A (2011) Monoclonal antibodies against betaamyloid (Abeta) for the treatment of Alzheimer’s disease:
The Abeta target at a crossroads. Expert Opin Biol Ther
11, 679-686.
Panza F, Frisardi V, Imbimbo BP, Seripa D, Paris F,
Santamato A, D’Onofrio G, Logroscino G, Pilotto A,
Solfrizzi V (2011) Anti-beta-amyloid immunotherapy
for Alzheimer’s disease: Focus on bapineuzumab. Curr
Alzheimer Res 8, 808-817.
Prins ND, Visser PJ, Scheltens P (2010) Can novel therapeutics halt the amyloid cascade? Alzheimers Res Ther
2, 5.
102
[1391]
[1392]
[1393]
[1394]
[1395]
[1396]
[1397]
[1398]
[1399]
[1400]
[1401]
[1402]
[1403]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Roher AE, Maarouf CL, Daugs ID, Kokjohn TA, Hunter
JM, Sabbagh MN, Beach TG (2011) Neuropathology and
amyloid-beta spectrum in a bapineuzumab immunotherapy recipient. J Alzheimers Dis 24, 315-325.
Zago W, Buttini M, Comery TA, Nishioka C, Gardai
SJ, Seubert P, Games D, Bard F, Schenk D, Kinney GG
(2012) Neutralization of Soluble, synaptotoxic amyloid
beta species by antibodies is epitope specific. J Neurosci
32, 2696-2702.
Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan
K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen
M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P,
Schenk D, Yednock T (2000) Peripherally administered
antibodies against amyloid beta-peptide enter the central
nervous system and reduce pathology in a mouse model
of Alzheimer disease. Nat Med 6, 916-919.
Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow
MR, Paul SM, DeMattos RB (2010) Safety and changes in
plasma and cerebrospinal fluid amyloid beta after a single
administration of an amyloid beta monoclonal antibody
in subjects with Alzheimer disease. Clin Neuropharmacol
33, 67-73.
Carlson C, Estergard W, Oh J, Suhy J, Jack CR Jr, Siemers
E, Barakos J (2011) Prevalence of asymptomatic vasogenic
edema in pretreatment Alzheimer’s disease study cohorts
from phase 3 trials of semagacestat and solanezumab.
Alzheimers Dement 7, 396-401.
Reichert JM (2011) Antibody-based therapeutics to watch
in 2011. MAbs 3, 76-99.
Samadi H, Sultzer D (2011) Solanezumab for Alzheimer’s
disease. Expert Opin Biol Ther 11, 787-798.
Imbimbo BP, Ottonello S, Frisardi V, Solfrizzi V, Greco
A, Seripa D, Pilotto A, Panza F (2012) Solanezumab for
the treatment of mild-to-moderate Alzheimer’s disease.
Expert Rev Clin Immunol 8, 135-149.
Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider
BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C,
Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers
ER (2012) Safety and biomarker effects of solanezumab
in patients with Alzheimer’s disease. Alzheimers Dement
8, 261-271.
Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F,
Bohrmann B, Brooks DJ, Klunk WE, Ashford E, Yoo
K, Xu ZX, Loetscher H, Santarelli L (2012) Mechanism
of amyloid removal in patients with Alzheimer disease
treated with gantenerumab. Arch Neurol 69, 198-207.
Bohrmann B, Baumann K, Benz J, Gerber F, Huber W,
Knoflach F, Messer J, Oroszlan K, Rauchenberger R,
Richter WF, Rothe C, Urban M, Bardroff M, Winter
M, Nordstedt C, Loetscher H (2012) Gantenerumab: A
novel human anti-abeta antibody demonstrates sustained
cerebral amyloid-beta binding and elicits cell-mediated
removal of human amyloid-beta. J Alzheimers Dis 28,
49-69.
Delrieu J, Ousset PJ, Vellas B (2012) Gantenerumab for the
treatment of Alzheimer’s disease. Expert Opin Biol Ther
12, 1077-1086.
Adolfsson O, Pihlgren M, Toni N, Varisco Y, Buccarello AL, Antoniello K, Lohmann S, Piorkowska K,
Gafner V, Atwal JK, Maloney J, Chen M, Gogineni
A, Weimer RM, Mortensen DL, Friesenhahn M, Ho
C, Paul R, Pfeifer A, Muhs A, Watts RJ (2012) An
effector-reduced anti-beta-amyloid (Abeta) antibody with
unique Abeta binding properties promotes neuroprotec-
[1404]
[1405]
[1406]
[1407]
[1408]
[1409]
[1410]
[1411]
[1412]
[1413]
[1414]
[1415]
[1416]
[1417]
tion and glial engulfment of Abeta. J Neurosci 32, 96779689.
Balakrishnan K, ndrei-Selmer LC, Selmer T, Bacher M,
Dodel R (2010) Comparison of intravenous immunoglobulins for naturally occurring autoantibodies against
amyloid-beta. J Alzheimers Dis 20, 135-143.
Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M,
Oertel W (2010) Intravenous immunoglobulins as a treatment for Alzheimer’s disease: Rationale and current
evidence. Drugs 70, 513-528.
Relkin NR (2008) Current state of immunotherapy for
Alzheimer’s disease. CNS Spectr 13, 39-41.
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C,
Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME
(2009) 18-Month study of intravenous immunoglobulin
for treatment of mild Alzheimer disease. Neurobiol Aging
30, 1728-1736.
Hughes RA, Dalakas MC, Cornblath DR, Latov N,
Weksler ME, Relkin N (2009) Clinical applications of
intravenous immunoglobulins in neurology. Clin Exp
Immunol 158(Suppl 1), 34-42.
Poetsch V, Neuhaus W, Noe CR (2010) Serum-derived
immunoglobulins neutralize adverse effects of amyloidbeta peptide on the integrity of a blood-brain barrier in
vitro model. J Alzheimers Dis 21, 303-314.
Poetsch V, Benani-Baiti B, Neuhaus W, Muchitsch EM,
Noe CR (2010) Serum-derived immunoglobulins alter
amyloid beta transport across a blood-brain barrier in vitro
model. Pharmazie 65, 267-273.
Lanz TA, Schachter JB (2008) Solid-phase extraction
enhances detection of beta-amyloid peptides in plasma
and enables Abeta quantification following passive immunization with Abeta antibodies. J Neurosci Methods 169,
16-22.
Ding JD, Johnson LV, Herrmann R, Farsiu S, Smith SG,
Groelle M, Mace BE, Sullivan P, Jamison JA, Kelly U,
Harrabi O, Bollini SS, Dilley J, Kobayashi D, Kuang B, Li
W, Pons J, Lin JC, Bowes RC (2011) Anti-amyloid therapy
protects against retinal pigmented epithelium damage and
vision loss in a model of age-related macular degeneration.
Proc Natl Acad Sci U S A 108, E279-E287.
Venkataramani V, Wirths O, Budka H, Hartig W,
Kovacs GG, Bayer TA (2012) Antibody 9D5 recognizes oligomeric pyroglutamate amyloid-beta in a fraction
of amyloid-beta deposits in Alzheimer’s disease without cross-reactivity with other protein aggregates. J
Alzheimers Dis 29, 361-371.
Atwal JK, Chen Y, Chiu C, Mortensen DL, Meilandt WJ,
Liu Y, Heise CE, Hoyte K, Luk W, Lu Y, Peng K, Wu P,
Rouge L, Zhang Y, Lazarus RA, Scearce-Levie K, Wang
W, Wu Y, Tessier-Lavigne M, Watts RJ (2011) A therapeutic antibody targeting BACE1 inhibits amyloid-beta
production in vivo. Sci Transl Med 3, 84ra43.
Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal
J, Elliott JM, Prabhu S, Watts RJ, Dennis MS (2011) Boosting brain uptake of a therapeutic antibody by reducing its
affinity for a transcytosis target. Sci Transl Med 3, 84ra44.
Boado RJ, Zhang Y, Wang Y, Pardridge WM (2009) Engineering and expression of a chimeric transferrin receptor
monoclonal antibody for blood-brain barrier delivery in
the mouse. Biotechnol Bioeng 102, 1251-1258.
Boado RJ, Zhou QH, Lu JZ, Hui EK, Pardridge WM (2010)
Pharmacokinetics and brain uptake of a genetically engineered bifunctional fusion antibody targeting the mouse
transferrin receptor. Mol Pharm 7, 237-244.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1418]
[1419]
[1420]
[1421]
[1422]
[1423]
[1424]
[1425]
[1426]
[1427]
[1428]
[1429]
[1430]
[1431]
[1432]
[1433]
Zhou QH, Fu A, Boado RJ, Hui EK, Lu JZ, Pardridge
WM (2011) Receptor-mediated abeta amyloid antibody
targeting to Alzheimer’s disease mouse brain. Mol Pharm
8, 280-285.
Zhou QH, Boado RJ, Hui EK, Lu JZ, Pardridge WM (2011)
Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion
protein. Drug Metab Dispos 39, 1149-1154.
Zhou QH, Boado RJ, Pardridge WM (2012) Selective
plasma pharmacokinetics and brain uptake in the mouse
of enzyme fusion proteins derived from species-specific
receptor-targeted antibodies. J Drug Target 20, 715-719.
Pardridge WM, Boado RJ (2012) Reengineering biopharmaceuticals for targeted delivery across the blood-brain
barrier. Methods Enzymol 503, 269-292.
Boado RJ, Pardridge WM (2011) The Trojan Horse liposome technology for nonviral gene transfer across the
blood-brain barrier. J Drug Deliv 2011, 296151.
Goldshmit Y, Matteo R, Sztal T, Ellett F, Frisca F, Moreno
K, Crombie D, Lieschke GJ, Currie PD, Sabbadini RA,
Pebay A (2012) Blockage of lysophosphatidic Acid signaling improves spinal cord injury outcomes. Am J Pathol
181, 978-992.
Solomon B, Koppel R, Hanan E, Katzav T (1996) Monoclonal antibodies inhibit in vitro fibrillar aggregation of
the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci
U S A 93, 452-455.
Solomon B, Koppel R, Frankel D, Hanan-Aharon E
(1997) Disaggregation of Alzheimer beta-amyloid by sitedirected mAb. Proc Natl Acad Sci U S A 94, 41094112.
Buttini M, Masliah E, Barbour R, Grajeda H, Motter
R, Johnson-Wood K, Khan K, Seubert P, Freedman S,
Schenk D, Games D (2005) Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of
Alzheimer’s disease. J Neurosci 25, 9096-9101.
Morgan D (2005) Mechanisms of A beta plaque clearance
following passive A beta immunization. Neurodegener Dis
2, 261-266.
Levites Y, Das P, Price RW, Rochette MJ, Kostura
LA, McGowan EM, Murphy MP, Golde TE (2006)
Anti-Abeta42- and anti-Abeta40-specific mAbs attenuate
amyloid deposition in an Alzheimer disease mouse model.
J Clin Invest 116, 193-201.
Levites Y, Smithson LA, Price RW, Dakin RS, Yuan B,
Sierks MR, Kim J, McGowan E, Reed DK, Rosenberry
TL, Das P, Golde TE (2006) Insights into the mechanisms
of action of anti-Abeta antibodies in Alzheimer’s disease
mouse models. FASEB J 20, 2576-2578.
Chang WP, Downs D, Huang XP, Da H, Fung KM, Tang
J (2007) Amyloid-beta reduction by memapsin 2 (betasecretase) immunization. FASEB J 21, 3184-3196.
Chauhan NB (2007) Intracerebroventricular passive immunization with anti-oligoAbeta antibody in
TgCRND8. J Neurosci Res 85, 451-463.
Gardberg AS, Dice LT, Ou S, Rich RL, Helmbrecht E,
Ko J, Wetzel R, Myszka DG, Patterson PH, Dealwis C
(2007) Molecular basis for passive immunotherapy of
Alzheimer’s disease. Proc Natl Acad Sci U S A 104, 1565915664.
Habicht G, Haupt C, Friedrich RP, Hortschansky P,
Sachse C, Meinhardt J, Wieligmann K, Gellermann GP,
Brodhun M, Gotz J, Halbhuber KJ, Rocken C, Horn U,
Fandrich M (2007) Directed selection of a conformational
antibody domain that prevents mature amyloid fibril for-
[1434]
[1435]
[1436]
[1437]
[1438]
[1439]
[1440]
[1441]
[1442]
[1443]
[1444]
[1445]
103
mation by stabilizing Abeta protofibrils. Proc Natl Acad
Sci U S A 104, 19232-19237.
Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool
S, Gurlo T, Butler P, Glabe CG (2007) Fibril specific,
conformation dependent antibodies recognize a generic
epitope common to amyloid fibrils and fibrillar oligomers
that is absent in prefibrillar oligomers. Mol Neurodegener
2, 18.
Kayed R, Canto I, Breydo L, Rasool S, Lukacsovich T,
Wu J, Albay R III, Pensalfini A, Yeung S, Head E, Marsh
JL, Glabe C (2010) Conformation dependent monoclonal
antibodies distinguish different replicating strains or conformers of prefibrillar Abeta oligomers. Mol Neurodegener
5, 57.
Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan
A, Petrushina I, Movsesyan N, Mina E, Kiyatkin A, Glabe
CG, Cribbs DH, Agadjanyan MG (2007) Anti-A beta 1-11
antibody binds to different beta-amyloid species, inhibits
fibril formation, and disaggregates preformed fibrils but
not the most toxic oligomers. J Biol Chem 282, 2237622386.
Moretto N, Bolchi A, Rivetti C, Imbimbo BP, Villetti
G, Pietrini V, Polonelli L, Del SS, Smith KM, Ferrante
RJ, Ottonello S (2007) Conformation-sensitive antibodies against alzheimer amyloid-beta by immunization with
a thioredoxin-constrained B-cell epitope peptide. J Biol
Chem 282, 11436-11445.
Poduslo JF, Ramakrishnan M, Holasek SS, RamirezAlvarado M, Kandimalla KK, Gilles EJ, Curran GL,
Wengenack TM (2007) In vivo targeting of antibody
fragments to the nervous system for Alzheimer’s disease immunotherapy and molecular imaging of amyloid
plaques. J Neurochem 102, 420-433.
Rakover I, Arbel M, Solomon B (2007) Immunotherapy
against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576
mice without a significant effect on brain abeta levels.
Neurodegener Dis 4, 392-402.
Song MS, Mook-Jung I, Lee HJ, Min JY, Park MH (2007)
Serum anti-amyloid-beta antibodies and Alzheimer’s disease in elderly Korean patients. J Int Med Res 35, 301-306.
Tampellini D, Magrane J, Takahashi RH, Li F, Lin MT,
Almeida CG, Gouras GK (2007) Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta
and protect against synaptic alterations. J Biol Chem 282,
18895-18906.
Bolukbasi Hatip FF, Matsunaga Y, Yamada T (2008) Specific reactivity of mild/severe Alzheimer’s disease patient’s
sera to antibody against Abeta1-40 epitope 17-21. Acta
Neurol Scand 117, 404-408.
Koenigsknecht-Talboo J, Meyer-Luehmann M, Parsadanian M, Garcia-Alloza M, Finn MB, Hyman BT, Bacskai
BJ, Holtzman DM (2008) Rapid microglial response
around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J Neurosci 28,
14156-14164.
Manea M, Kalaszi A, Mezo G, Horvati K, Bodor A, Horvath A, Farkas O, Perczel A, Przybylski M, Hudecz F
(2008) Antibody recognition and conformational flexibility of a plaque-specific beta-amyloid epitope modulated
by non-native peptide flanking regions. J Med Chem 51,
1150-1161.
Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido
T, Gill D, Basi G, Schenk D, Seubert P, Games D (2008)
104
[1446]
[1447]
[1448]
[1449]
[1450]
[1451]
[1452]
[1453]
[1454]
[1455]
[1456]
[1457]
[1458]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Immunotherapy reduces vascular amyloid-beta in PDAPP
mice. J Neurosci 28, 6787-6793.
Tucker SM, Borchelt DR, Troncoso JC (2008) Limited
clearance of pre-existing amyloid plaques after intracerebral injection of Abeta antibodies in two mouse models of
Alzheimer disease. J Neuropathol Exp Neurol 67, 30-40.
Xu W, Kawarabayashi T, Matsubara E, Deguchi K,
Murakami T, Harigaya Y, Ikeda M, Amari M, Kuwano R,
Abe K, Shoji M (2008) Plasma antibodies to Abeta40 and
Abeta42 in patients with Alzheimer’s disease and normal
controls. Brain Res 1219, 169-179.
Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S, Ito H
(2009) Improvement of cerebral function by anti-amyloid
precursor protein antibody infusion after traumatic brain
injury in rats. Mol Cell Biochem 324, 191-199.
Lord A, Gumucio A, Englund H, Sehlin D, Sundquist VS,
Soderberg L, Moller C, Gellerfors P, Lannfelt L, Pettersson
FE, Nilsson LN (2009) An amyloid-beta protofibrilselective antibody prevents amyloid formation in a mouse
model of Alzheimer’s disease. Neurobiol Dis 36, 425-434.
Rozkalne A, Spires-Jones TL, Stern EA, Hyman BT
(2009) A single dose of passive immunotherapy has
extended benefits on synapses and neurites in an Alzheimer’s disease mouse model. Brain Res 1280, 178-185.
Spires-Jones TL, Mielke ML, Rozkalne A, MeyerLuehmann M, de CA, Bacskai BJ, Schenk D, Hyman BT
(2009) Passive immunotherapy rapidly increases structural
plasticity in a mouse model of Alzheimer disease. Neurobiol Dis 33, 213-220.
Xu YX, Wang HQ, Yan J, Sun XB, Guo JC, Zhu CQ (2009)
Antibody binding to cell surface amyloid precursor protein
induces neuronal injury by deregulating the phosphorylation of focal adhesion signaling related proteins. Neurosci
Lett 465, 276-281.
Ying Z, Xin W, Jin-Sheng H, Fu-Xiang B, Wei-Min S,
Xin-Xian D, Xiao-Bo W, Yi-Qin L, Xian-Xian Z, HongGang H, Xiang-Lei P, Yan-Peng Z, Ling-Ling H, Tao H
(2009) Preparation and characterization of a monoclonal
antibody with high affinity for soluble Abeta oligomers.
Hybridoma (Larchmt) 28, 349-354.
Axelsen TV, Holm A, Birkelund S, Christiansen G, Ploug
M, Holm IE (2009) Specific recognition of the C-terminal
end of A beta 42 by a high affinity monoclonal antibody.
Mol Immunol 46, 2267-2273.
Adekar SP, Klyubin I, Macy S, Rowan MJ, Solomon
A, Dessain SK, O’Nuallain B (2010) Inherent antiamyloidogenic activity of human immunoglobulin gamma
heavy chains. J Biol Chem 285, 1066-1074.
Basi GS, Feinberg H, Oshidari F, Anderson J, Barbour
R, Baker J, Comery TA, Diep L, Gill D, Johnson-Wood
K, Goel A, Grantcharova K, Lee M, Li J, Partridge A,
Griswold-Prenner I, Piot N, Walker D, Widom A, Pangalos MN, Seubert P, Jacobsen JS, Schenk D, Weis WI
(2010) Structural correlates of antibodies associated with
acute reversal of amyloid beta-related behavioral deficits
in a mouse model of Alzheimer disease. J Biol Chem 285,
3417-3427.
Luo F, Rustay NR, Seifert T, Roesner B, Hradil V, Hillen
H, Ebert U, Severin JM, Cox BF, Llano DA, Day M,
Fox GB (2010) Magnetic resonance imaging detection
and time course of cerebral microhemorrhages during passive immunotherapy in living amyloid precursor protein
transgenic mice. J Pharmacol Exp Ther 335, 580-588.
Szabo P, Mujalli DM, Rotondi ML, Sharma R, Weber
A, Schwarz HP, Weksler ME, Relkin N (2010) Measure-
[1459]
[1460]
[1461]
[1462]
[1463]
[1464]
[1465]
[1466]
[1467]
[1468]
[1469]
[1470]
ment of anti-beta amyloid antibodies in human blood.
J Neuroimmunol 227, 167-174.
Winkler DT, Abramowski D, Danner S, Zurini M,
Paganetti P, Tolnay M, Staufenbiel M (2010) Rapid cerebral amyloid binding by Abeta antibodies infused into
beta-amyloid precursor protein transgenic mice. Biol Psychiatry 68, 971-974.
Lindhagen-Persson M, Brannstrom K, Vestling M, Steinitz
M, Olofsson A (2010) Amyloid-beta oligomer specificity mediated by the IgM isotype–implications for a
specific protective mechanism exerted by endogenous
auto-antibodies. PLoS One 5, e13928.
Miller DL, Potempska A, Wegiel J, Mehta PD (2011)
High-affinity rabbit monoclonal antibodies specific for
amyloid peptides amyloid-beta40 and amyloid-beta42.
J Alzheimers Dis 23, 293-305.
Zhang Y, He JS, Wang X, Wang J, Bao FX, Pang SY,
Yin F, Hu HG, Peng XL, Sun WM, Zheng YP, Hou LL,
Hong T (2011) Administration of amyloid-beta42
oligomer-specific monoclonal antibody improved memory performance in SAMP8 mice. J Alzheimers Dis 23,
551-561.
O’Nuallain B, Klyubin I, Mc Donald JM, Foster JS, Welzel
A, Barry A, Dykoski RK, Cleary JP, Gebbink MF, Rowan
MJ, Walsh DM (2011) A monoclonal antibody against synthetic Abeta dimer assemblies neutralizes brain-derived
synaptic plasticity-disrupting Abeta. J Neurochem 119,
189-201.
Dodel R, Balakrishnan K, Keyvani K, Deuster O, Neff F,
ndrei-Selmer LC, Roskam S, Stuer C, Al-Abed Y, Noelker
C, Balzer-Geldsetzer M, Oertel W, Du Y, Bacher M (2011)
Naturally occurring autoantibodies against beta-amyloid:
Investigating their role in transgenic animal and in vitro
models of Alzheimer’s disease. J Neurosci 31, 58475854.
Tanaka K, Nishimura M, Yamaguchi Y, Hashiguchi S,
Takiguchi S, Yamaguchi M, Tahara H, Gotanda T, Abe
R, Ito Y, Sugimura K (2011) A mimotope peptide of
Abeta42 fibril-specific antibodies with Abeta42 fibrillation
inhibitory activity induces anti-Abeta42 conformer antibody response by a displayed form on an M13 phage in
mice. J Neuroimmunol 236, 27-38.
Morgado I, Wieligmann K, Bereza M, Ronicke R,
Meinhardt K, Annamalai K, Baumann M, Wacker J,
Hortschansky P, Malesevic M, Parthier C, Mawrin C,
Schiene-Fischer C, Reymann KG, Stubbs MT, Balbach J,
Gorlach M, Horn U, Fandrich M (2012) Molecular basis
of beta-amyloid oligomer recognition with a conformational antibody fragment. Proc Natl Acad Sci U S A 109,
12503-12508.
Dorothee G, Bottlaender M, Moukari E, de Souza LC,
Maroy R, Corlier F, Colliot O, Chupin M, Lamari F,
Lehericy S, Dubois B, Sarazin M, Aucouturier P (2012)
Distinct patterns of antiamyloid-beta antibodies in typical
and atypical Alzheimer disease. Arch Neurol 69, 11811185.
Arbel M, Solomon B (2007) A novel immunotherapy for
Alzheimer’s disease: Antibodies against the beta-secretase
cleavage site of APP. Curr Alzheimer Res 4, 437-445.
Arbel M, Solomon B (2007) Immunotherapy for
Alzheimer’s disease: Attacking amyloid-beta from the
inside. Trends Immunol 28, 511-513.
Britschgi M, Wyss-Coray T (2007) Systemic and acquired
immune responses in Alzheimer’s disease. Int Rev Neurobiol 82, 205-233.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1471]
[1472]
[1473]
[1474]
[1475]
[1476]
[1477]
[1478]
[1479]
[1480]
[1481]
[1482]
[1483]
[1484]
[1485]
[1486]
[1487]
Cardinale A, Biocca S (2008) The potential of intracellular
antibodies for therapeutic targeting of protein-misfolding
diseases. Trends Mol Med 14, 373-380.
Lichtlen P, Mohajeri MH (2008) Antibody-based
approaches in Alzheimer’s research: Safety, pharmacokinetics, metabolism, and analytical tools. J Neurochem 104,
859-874.
Bednar MM (2009) Anti-amyloid antibody drugs in clinical testing for Alzheimer’s disease. IDrugs 12, 566575.
Jicha GA (2009) Is passive immunization for Alzheimer’s
disease ‘alive and well’ or ‘dead and buried’? Expert Opin
Biol Ther 9, 481-491.
Lambert MP, Velasco PT, Viola KL, Klein WL (2009) Targeting generation of antibodies specific to conformational
epitopes of amyloid beta-derived neurotoxins. CNS Neurol
Disord Drug Targets 8, 65-81.
Pul R, Dodel R, Stangel M (2011) Antibody-based therapy
in Alzheimer’s disease. Expert Opin Biol Ther 11, 343357.
Hermann DM, Keyvani K, van de NJ, Weimar C, Wiltfang
J, Nitsch RM, Szodorai A (2011) Brain-reactive betaamyloid antibodies in primary CNS angiitis with cerebral
amyloid angiopathy. Neurology 77, 503-505.
Merlini G (2011) Reducing the amyloid burden through
immunotherapy: A major therapeutic advance. Nephrol
Dial Transplant 26, 1471-1473.
Perchiacca JM, Ladiwala AR, Bhattacharya M, Tessier
PM (2012) Structure-based design of conformation- and
sequence-specific antibodies against amyloid beta. Proc
Natl Acad Sci U S A 109, 84-89.
Liu YH, Giunta B, Zhou HD, Tan J, Wang YJ (2012)
Immunotherapy for Alzheimer disease-the challenge of
adverse effects. Nat Rev Neurol 8, 465-469.
Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos
RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM,
Paul SM (2002) Immunization reverses memory deficits
without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 5, 452-457.
Yamada K, Yabuki C, Seubert P, Schenk D, Hori Y, Ohtsuki S, Terasaki T, Hashimoto T, Iwatsubo T (2009) Abeta
immunotherapy: Intracerebral sequestration of Abeta by
an anti-Abeta monoclonal antibody 266 with high affinity
to soluble Abeta. J Neurosci 29, 11393-11398.
Freeman GB, Lin JC, Pons J, Raha NM (2012) 39week toxicity and toxicokinetic study of ponezumab
(PF-04360365) in cynomolgus monkeys with 12-week
recovery period. J Alzheimers Dis 28, 531-541.
Freeman GB, Brown TP, Wallace K, Bales KR (2012)
Chronic administration of an aglycosylated murine antibody of ponezumab does not worsen microhemorrhages
in aged Tg2576 mice. Curr Alzheimer Res, [Epub ahead
of print].
La Porte SL, Bollini SS, Lanz TA, Abdiche YN, Rusnak
AS, Ho WH, Kobayashi D, Harrabi O, Pappas D, Mina
EW, Milici AJ, Kawabe TT, Bales K, Lin JC, Pons J
(2012) Structural basis of C-terminal beta-amyloid peptide binding by the antibody ponezumab for the treatment
of Alzheimer’s disease. J Mol Biol 421, 525-536.
Crespo-Biel N, Theunis C, Van Leuven F (2012) Protein
tau: Prime cause of synaptic and neuronal degeneration in Alzheimer’s disease. Int J Alzheimers Dis 2012,
251426.
Morris M, Maeda S, Vossel K, Mucke L (2011) The many
faces of tau. Neuron 70, 410-426.
[1488]
[1489]
[1490]
[1491]
[1492]
[1493]
[1494]
[1495]
[1496]
[1497]
[1498]
[1499]
[1500]
[1501]
[1502]
105
Kolarova M, Garcia-Sierra F, Bartos A, Ricny J, Ripova D
(2012) Structure and pathology of tau protein in Alzheimer
disease. Int J Alzheimers Dis 2012, 731526.
Mandelkow EM, Mandelkow E (2012) Biochemistry and
cell biology of tau protein in neurofibrillary degeneration.
Cold Spring Harb Perspect Med 2, a006247.
Lee VM, Brunden KR, Hutton M, Trojanowski JQ
(2011) Developing therapeutic approaches to tau, selected
kinases, and related neuronal protein targets. Cold Spring
Harb Perspect Med 1, a006437.
Santacruz K, Lewis J, Spires T, Paulson J, Kotilinek
L, Ingelsson M, Guimaraes A, DeTure M, Ramsden M,
McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH
(2005) Tau suppression in a neurodegenerative mouse
model improves memory function. Science 309, 476481.
Berger Z, Roder H, Hanna A, Carlson A, Rangachari V,
Yue M, Wszolek Z, Ashe K, Knight J, Dickson D, Andorfer
C, Rosenberry TL, Lewis J, Hutton M, Janus C (2007)
Accumulation of pathological tau species and memory loss
in a conditional model of tauopathy. J Neurosci 27, 36503662.
Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2012)
Abnormal hyperphosphorylation of tau: Sites, regulation,
and molecular mechanism of neurofibrillary degeneration.
J Alzheimers Dis, doi: 10.3233/JAD-2012-129031 [Epub
ahead of print].
Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Yardin C, Terro F (2012) Tau protein kinases:
Involvement in Alzheimer’s disease. Ageing Res Rev 12,
289-309.
Bekris LM, Millard S, Lutz F, Li G, Galasko DR, Farlow
MR, Quinn JF, Kaye JA, Leverenz JB, Tsuang DW, Yu CE,
Peskind ER (2012) Tau phosphorylation pathway genes
and cerebrospinal fluid tau levels in Alzheimer’s disease.
Am J Med Genet B Neuropsychiatr Genet 159B, 874-883.
Kester MI, van d V, Blankenstein MA, Pijnenburg YA,
van Elk EJ, Scheltens P, van der Flier WM (2009) CSF
biomarkers predict rate of cognitive decline in Alzheimer
disease. Neurology 73, 1353-1358.
Ittner LM, Gotz J (2011) Amyloid-beta and tau–a toxic
pas de deux in Alzheimer’s disease. Nat Rev Neurosci 12,
65-72.
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van EJ,
Wolfing H, Chieng BC, Christie MJ, Napier IA, Eckert A,
Staufenbiel M, Hardeman E, Gotz J (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s
disease mouse models. Cell 142, 387-397.
Ittner A, Ke YD, van EJ, Gladbach A, Gotz J, Ittner LM
(2011) Brief update on different roles of tau in neurodegeneration. IUBMB Life 63, 495-502.
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan
F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels
JL, Mucke L (2011) Amyloid-beta/Fyn-induced synaptic,
network, and cognitive impairments depend on tau levels in
multiple mouse models of Alzheimer’s disease. J Neurosci
31, 700-711.
Gotz J, Ittner A, Ittner LM (2012) Tau-targeted treatment
strategies in Alzheimer’s disease. Br J Pharmacol 165,
1246-1259.
Mondragon-Rodriguez S, Perry G, Zhu X, Boehm J (2012)
Amyloid Beta and tau proteins as therapeutic targets for
Alzheimer’s disease treatment: Rethinking the current
strategy. Int J Alzheimers Dis 2012, 630182.
106
[1503]
[1504]
[1505]
[1506]
[1507]
[1508]
[1509]
[1510]
[1511]
[1512]
[1513]
[1514]
[1515]
[1516]
[1517]
[1518]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, SpiresJones TL, Hyman BT (2012) The synaptic accumulation of
hyperphosphorylated tau oligomers in Alzheimer disease
is associated with dysfunction of the ubiquitin-proteasome
system. Am J Pathol 181, 1426-1435.
Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS,
Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s
pathological cascade. Lancet Neurol 9, 119-128.
Jack CR Jr, Vemuri P, Wiste HJ, Weigand SD, Aisen PS,
Trojanowski JQ, Shaw LM, Bernstein MA, Petersen RC,
Weiner MW, Knopman DS (2011) Evidence for ordering
of Alzheimer disease biomarkers. Arch Neurol 68, 15261535.
Jack CR Jr, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG,
Lowe V, Kantarci K, Bernstein MA, Senjem ML, Gunter
JL, Boeve BF, Trojanowski JQ, Shaw LM, Aisen PS,
Weiner MW, Petersen RC, Knopman DS (2012) Shapes
of the trajectories of 5 major biomarkers of Alzheimer
disease. Arch Neurol 69, 856-867.
Han SD, Gruhl J, Beckett L, Dodge HH, Stricker NH,
Farias S, Mungas D (2012) Beta amyloid, tau, neuroimaging, and cognition: Sequence modeling of biomarkers
for Alzheimer’s disease. Brain Imaging Behav, doi:
10.1007/s11682-012-9177-0 [Epub ahead of print].
Wischik CM, Bentham P, Wishik DJ, SK (2008) Tau
aggregation inhibitor (TAI) therapy with Rember™ arrests
disease progression in mild to moderate Alzheimer’s disease over 50 weeks. Alzheimers Dementia 4, T167.
Wischik C, Staff R (2009) Challenges in the conduct of
disease-modifying trials in AD: Practical experience from
a phase 2 trial of Tau-aggregation inhibitor therapy. J Nutr
Health Aging 13, 367-369.
Wischik CM, Edwards PC, Lai RY, Roth M, Harrington
CR (1996) Selective inhibition of Alzheimer disease-like
tau aggregation by phenothiazines. Proc Natl Acad Sci
U S A 93, 11213-11218.
Atamna H, Nguyen A, Schultz C, Boyle K, Newberry J,
Kato H, Ames BN (2008) Methylene blue delays cellular
senescence and enhances key mitochondrial biochemical
pathways. FASEB J 22, 703-712.
Oz M, Lorke DE, Petroianu GA (2009) Methylene blue and
Alzheimer’s disease. Biochem Pharmacol 78, 927-932.
Oz M, Lorke DE, Hasan M, Petroianu GA (2011) Cellular
and molecular actions of Methylene Blue in the nervous
system. Med Res Rev 31, 93-117.
Oz M, Isaev D, Lorke DE, Hasan M, Petroianu G, Shippenberg TS (2012) Methylene blue inhibits function of the
5-HT transporter. Br J Pharmacol 166, 168-176.
Atamna H, Kumar R (2010) Protective role of methylene blue in Alzheimer’s disease via mitochondria and
cytochrome c oxidase. J Alzheimers Dis 20(Suppl 2),
S439-S452.
Schirmer RH, Adler H, Pickhardt M, Mandelkow E (2011)
“Lest we forget you–methylene blue...”. Neurobiol Aging
32, 2325-2316.
O’Leary JC, Li Q III, Marinec P, Blair LJ, Congdon EE,
Johnson AG, Jinwal UK, Koren J III, Jones JR, Kraft C,
Peters M, Abisambra JF, Duff KE, Weeber EJ, Gestwicki
JE, Dickey CA (2010) Phenothiazine-mediated rescue of
cognition in tau transgenic mice requires neuroprotection
and reduced soluble tau burden. Mol Neurodegener 5, 45.
Medina DX, Caccamo A, Oddo S (2011) Methylene blue
reduces abeta levels and rescues early cognitive deficit by
increasing proteasome activity. Brain Pathol 21, 140-149.
[1519]
[1520]
[1521]
[1522]
[1523]
[1524]
[1525]
[1526]
[1527]
[1528]
[1529]
[1530]
[1531]
[1532]
[1533]
Necula M, Breydo L, Milton S, Kayed R, van d V, Tone P,
Glabe CG (2007) Methylene blue inhibits amyloid Abeta
oligomerization by promoting fibrillization. Biochemistry
46, 8850-8860.
del Ser T, Steinwachs KC, Gertz HJ, Andres MV, GomezCarrillo B, Medina M, Vericat JA, Redondo P, Fleet
D, Leon T (2012) Treatment of Alzheimer’s disease
with the GSK-3 inhibitor tideglusib: A pilot study. J
Alzheimers Dis, doi: 10.3233/JAD-2012-120805 [Epub
ahead of print].
Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB (2010) Selective interaction of lansoprazole and
astemizole with tau polymers: Potential new clinical use
in diagnosis of Alzheimer’s disease. J Alzheimers Dis 19,
573-589.
Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M,
Starkova N, Calingasan NY, Yang L, Tampellini D, Starkov
AA, Chan RB, Di PG, Pujol A, Beal MF (2012) Bezafibrate administration improves behavioral deficits and tau
pathology in P301S mice. Hum Mol Genet 21, 5091-5105.
Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS,
Hogan AM, Iba M, James MJ, Xie SX, Ballatore C, Smith
AB III, Lee VM, Trojanowski JQ (2010) Epothilone D
improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci
30, 13861-13866.
Yang Y, Ma D, Wang Y, Jiang T, Hu S, Zhang M, Yu
X, Gong CX (2012) Intranasal insulin ameliorates tau
hyperphosphorylation in a rat model of type 2 diabetes.
J Alzheimers Dis, doi: 10.3233/JAD-2012-121294-2012
[Epub ahead of print].
Taghavi A, Nasir S, Pickhardt M, Heyny-von Haussen R,
Mall G, Mandelkow E, Mandelkow EM, Schmidt B (2011)
N -benzylidene-benzohydrazides as novel and selective
tau-PHF ligands. J Alzheimers Dis 27, 835-843.
Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Terro F (2012) Tau protein phosphatases in
Alzheimer’s disease: The leading role of PP2A. Ageing
Res Rev 12, 39-49.
Braithwaite SP, Stock JB, Lombroso PJ, Nairn AC (2012)
Protein phosphatases and Alzheimer’s disease. Prog Mol
Biol Transl Sci 106, 343-379.
van Eersel J, Ke YD, Liu X, Delerue F, Kril JJ, Gotz J,
Ittner LM (2010) Sodium selenate mitigates tau pathology,
neurodegeneration, and functional deficits in Alzheimer’s
disease models. Proc Natl Acad Sci U S A 107, 1388813893.
Yuzwa SA, Macauley MS, Heinonen JE, Shan X,
Dennis RJ, He Y, Whitworth GE, Stubbs KA, McEachern EJ, Davies GJ, Vocadlo DJ (2008) A potent
mechanism-inspired O-GlcNAcase inhibitor that blocks
phosphorylation of tau in vivo. Nat Chem Biol 4, 483-490.
Yuzwa SA, Vocadlo DJ (2009) O-GlcNAc modification
and the tauopathies: Insights from chemical biology. Curr
Alzheimer Res 6, 451-454.
Yuzwa SA, Yadav AK, Skorobogatko Y, Clark T, Vosseller
K, Vocadlo DJ (2011) Mapping O-GlcNAc modification
sites on tau and generation of a site-specific O-GlcNAc tau
antibody. Amino Acids 40, 857-868.
Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko
Y, Vosseller K, Vocadlo DJ (2012) Increasing O-GlcNAc
slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol 8, 393-399.
Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ (2012)
Insights into O-GlcNAc processing and dynamics
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1534]
[1535]
[1536]
[1537]
[1538]
[1539]
[1540]
[1541]
[1542]
[1543]
[1544]
[1545]
[1546]
[1547]
[1548]
[1549]
through kinetic analysis of O-GlcNAc transferase and
O-GlcNAcase activity on protein substrates. J Biol Chem
287, 15395-15408.
Fischer PM (2008) Turning down tau phosphorylation. Nat
Chem Biol 4, 448-449.
Lefebvre T (2012) Recall sugars, forget Alzheimer’s.
Nature Chem Biol 8, 325-326.
Navarrete LP, Perez P, Morales I, Maccioni RB (2011)
Novel drugs affecting tau behavior in the treatment of
Alzheimer’s disease and tauopathies. Curr Alzheimer Res
8, 678-685.
Navarrete LP, Guzman L, San MA, studillo-Saavedra L,
Maccioni RB (2012) Molecules of the quinoline family
block tau self-aggregation: Implications toward a therapeutic approach for Alzheimer’s disease. J Alzheimers Dis
29, 79-88.
Calcul L, Zhang B, Jinwal UK, Dickey CA, Baker BJ
(2012) Natural products as a rich source of tau-targeting
drugs for Alzheimer’s disease. Future Med Chem 4, 17511761.
Chirita C, Necula M, Kuret J (2004) Ligand-dependent
inhibition and reversal of tau filament formation. Biochemistry 43, 2879-2887.
Necula M, Chirita CN, Kuret J (2005) Cyanine dye N744
inhibits tau fibrillization by blocking filament extension:
Implications for the treatment of tauopathic neurodegenerative diseases. Biochemistry 44, 10227-10237.
Pickhardt M, von BM, Gazova Z, Hascher A, Biernat
J, Mandelkow EM, Mandelkow E (2005) Screening for
inhibitors of tau polymerization. Curr Alzheimer Res 2,
219-226.
Pickhardt M, Gazova Z, von BM, Khlistunova I, Wang
Y, Hascher A, Mandelkow EM, Biernat J, Mandelkow E
(2005) Anthraquinones inhibit tau aggregation and dissolve Alzheimer’s paired helical filaments in vitro and in
cells. J Biol Chem 280, 3628-3635.
Khlistunova I, Biernat J, Wang Y, Pickhardt M, von
BM, Gazova Z, Mandelkow E, Mandelkow EM (2006)
Inducible expression of Tau repeat domain in cell models of tauopathy: Aggregation is toxic to cells but can be
reversed by inhibitor drugs. J Biol Chem 281, 1205-1214.
Bulic B, Pickhardt M, Khlistunova I, Biernat J, Mandelkow
EM, Mandelkow E, Waldmann H (2007) Rhodanine-based
tau aggregation inhibitors in cell models of tauopathy.
Angew Chem Int Ed Engl 46, 9215-9219.
Khlistunova I, Pickhardt M, Biernat J, Wang Y, Mandelkow EM, Mandelkow E (2007) Inhibition of tau
aggregation in cell models of tauopathy. Curr Alzheimer
Res 4, 544-546.
Pickhardt M, Larbig G, Khlistunova I, Coksezen A, Meyer
B, Mandelkow EM, Schmidt B, Mandelkow E (2007)
Phenylthiazolyl-hydrazide and its derivatives are potent
inhibitors of tau aggregation and toxicity in vitro and in
cells. Biochemistry 46, 10016-10023.
Pickhardt M, Biernat J, Khlistunova I, Wang YP, Gazova
Z, Mandelkow EM, Mandelkow E (2007) N-phenylamine
derivatives as aggregation inhibitors in cell models of
tauopathy. Curr Alzheimer Res 4, 397-402.
Crowe A, Ballatore C, Hyde E, Trojanowski JQ, Lee
VM (2007) High throughput screening for small molecule
inhibitors of heparin-induced tau fibril formation. Biochem
Biophys Res Commun 358, 1-6.
Honson NS, Jensen JR, Darby MV, Kuret J (2007) Potent
inhibition of tau fibrillization with a multivalent ligand.
Biochem Biophys Res Commun 363, 229-234.
[1550]
[1551]
[1552]
[1553]
[1554]
[1555]
[1556]
[1557]
[1558]
[1559]
[1560]
[1561]
[1562]
[1563]
[1564]
107
Larbig G, Pickhardt M, Lloyd DG, Schmidt B, Mandelkow
E (2007) Screening for inhibitors of tau protein aggregation into Alzheimer paired helical filaments: A ligand
based approach results in successful scaffold hopping.
Curr Alzheimer Res 4, 315-323.
Bulic B, Pickhardt M, Schmidt B, Mandelkow EM,
Waldmann H, Mandelkow E (2009) Development of tau
aggregation inhibitors for Alzheimer’s disease. Angew
Chem Int Ed Engl 48, 1740-1752.
Chang E, Congdon EE, Honson NS, Duff KE, Kuret J
(2009) Structure-activity relationship of cyanine tau aggregation inhibitors. J Med Chem 52, 3539-3547.
Chang E, Honson NS, Bandyopadhyay B, Funk KE, Jensen
JR, Kim S, Naphade S, Kuret J (2009) Modulation and
detection of tau aggregation with small-molecule ligands.
Curr Alzheimer Res 6, 409-414.
Crowe A, Huang W, Ballatore C, Johnson RL, Hogan
AM, Huang R, Wichterman J, McCoy J, Huryn D,
Auld DS, Smith AB III, Inglese J, Trojanowski JQ,
Austin CP, Brunden KR, Lee VM (2009) Identification of
aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry 48, 77327745.
Honson NS, Jensen JR, Abraha A, Hall GF, Kuret J (2009)
Small-molecule mediated neuroprotection in an in situ
model of tauopathy. Neurotox Res 15, 274-283.
Ballatore C, Brunden KR, Piscitelli F, James MJ, Crowe
A, Yao Y, Hyde E, Trojanowski JQ, Lee VM, Smith AB
III (2010) Discovery of brain-penetrant, orally bioavailable aminothienopyridazine inhibitors of tau aggregation.
J Med Chem 53, 3739-3747.
Bulic B, Pickhardt M, Mandelkow EM, Mandelkow E
(2010) Tau protein and tau aggregation inhibitors. Neuropharmacology 59, 276-289.
Schafer KN, Murale DP, Kim K, Cisek K, Kuret J,
Churchill DG (2011) Structure-activity relationship of
cyclic thiacarbocyanine tau aggregation inhibitors. Bioorg
Med Chem Lett 21, 3273-3276.
Martin L, Magnaudeix A, Wilson CM, Yardin C, Terro F
(2011) The new indirubin derivative inhibitors of glycogen
synthase kinase-3, 6-BIDECO and 6-BIMYEO, prevent
tau phosphorylation and apoptosis induced by the inhibition of protein phosphatase-2A by okadaic acid in cultured
neurons. J Neurosci Res 89, 1802-1811.
Ballatore C, Crowe A, Piscitelli F, James M, Lou K, Rossidivito G, Yao Y, Trojanowski JQ, Lee VM, Brunden KR,
Smith AB III (2012) Aminothienopyridazine inhibitors of
tau aggregation: Evaluation of structure-activity relationship leads to selection of candidates with desirable in vivo
properties. Bioorg Med Chem 20, 4451-4461.
Ballatore C, Brunden KR, Huryn DM, Trojanowski JQ,
Lee VM, Smith AB III (2012) Microtubule stabilizing
agents as potential treatment for Alzheimer’s disease and
related neurodegenerative tauopathies. J Med Chem 55,
8979-8996.
Castro A, Martinez A (2000) Inhibition of tau phosphorylation: A new therapeutic strategy for the treatment of
Alzheimer’s disease and other neurodegenerative disorders. Expert Opin Ther Patents 10, 1519-1527.
Lau LF, Schachter JB, Seymour PA, Sanner MA (2002)
Tau protein phosphorylation as a therapeutic target in
Alzheimer’s disease. Curr Top Med Chem 2, 395-415.
Dickey CA, Petrucelli L (2006) Current strategies for the
treatment of Alzheimer’s disease and other tauopathies.
Expert Opin Ther Targets 10, 665-676.
108
[1565]
[1566]
[1567]
[1568]
[1569]
[1570]
[1571]
[1572]
[1573]
[1574]
[1575]
[1576]
[1577]
[1578]
[1579]
[1580]
[1581]
[1582]
[1583]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Ballatore C, Lee VM, Trojanowski JQ (2007) Taumediated neurodegeneration in Alzheimer’s disease and
related disorders. Nat Rev Neurosci 8, 663-672.
Gong CX, Iqbal K (2008) Hyperphosphorylation of
microtubule-associated protein tau: A promising therapeutic target for Alzheimer disease. Curr Med Chem 15,
2321-2328.
Honson NS, Kuret J (2008) Tau aggregation and toxicity
in tauopathic neurodegenerative diseases. J Alzheimers Dis
14, 417-422.
Iqbal K, Grundke-Iqbal I (2008) Alzheimer neurofibrillary
degeneration: Significance, etiopathogenesis, therapeutics
and prevention. J Cell Mol Med 12, 38-55.
Schneider A, Mandelkow E (2008) Tau-based treatment
strategies in neurodegenerative diseases. Neurotherapeutics 5, 443-457.
Brunden KR, Trojanowski JQ, Lee VM (2009) Advances
in tau-focused drug discovery for Alzheimer’s disease and
related tauopathies. Nat Rev Drug Discov 8, 783-793.
Hanger DP, Anderton BH, Noble W (2009) Tau phosphorylation: The therapeutic challenge for neurodegenerative
disease. Trends Mol Med 15, 112-119.
Brunden KR, Ballatore C, Crowe A, Smith AB III, Lee
VM, Trojanowski JQ (2010) Tau-directed drug discovery
for Alzheimer’s disease and related tauopathies: A focus
on tau assembly inhibitors. Exp Neurol 223, 304-310.
Gong CX, Grundke-Iqbal I, Iqbal K (2010) Targeting tau
protein in Alzheimer’s disease. Drugs Aging 27, 351-365.
Meraz-Rios MA, Lira-De Leon KI, Campos-Pena V,
De Anda-Hernandez MA, Mena-Lopez R (2010) Tau
oligomers and aggregation in Alzheimer’s disease. J Neurochem 112, 1353-1367.
Ballatore C, Brunden KR, Trojanowski JQ, Lee VM, Smith
AB, Huryn DM (2011) Modulation of protein-protein
interactions as a therapeutic strategy for the treatment of
neurodegenerative tauopathies. Curr Top Med Chem 11,
317-330.
Corbo CP, Alonso AC (2011) Therapeutic targets in
Alzheimer’s disease and related tauopathies. Prog Mol Biol
Transl Sci 98, 47-83.
Noble W, Pooler AM, Hanger DP (2011) Advances in taubased drug discovery. Expert Opin Drug Discov 6, 797810.
Fuentes P, Catalan J (2011) A clinical perspective: Anti
tau’s treatment in Alzheimer’s disease. Curr Alzheimer Res
8, 686-688.
Himmelstein DS, Ward SM, Lancia JK, Patterson KR,
Binder LI (2012) Tau as a therapeutic target in neurodegenerative disease. Pharmacol Ther 136, 8-22.
Ward SM, Himmelstein DS, Lancia JK, Binder LI (2012)
Tau oligomers and tau toxicity in neurodegenerative disease. Biochem Soc Trans 40, 667-671.
Karakaya T, Fusser F, Prvulovic D, Hampel H (2012)
Treatment options for tauopathies. Curr Treat Options
Neurol 14, 126-136.
Miller Y, Ma B, Nussinov R (2011) Synergistic interactions
between repeats in tau protein and Abeta amyloids may be
responsible for accelerated aggregation via polymorphic
states. Biochemistry 50, 5172-5181.
Zhang W, Arteaga J, Cashion DK, Chen G, Gangadharmath U, Gomez LF, Kasi D, Lam C, Liang Q, Liu C,
Mocharla VP, Mu F, Sinha A, Szardenings AK, Wang
E, Walsh JC, Xia C, Yu C, Zhao T, Kolb HC (2012) A
highly selective and specific PET tracer for imaging of tau
pathologies. J Alzheimers Dis 31, 601-612.
[1584]
[1585]
[1586]
[1587]
[1588]
[1589]
[1590]
[1591]
[1592]
[1593]
[1594]
[1595]
[1596]
[1597]
Fodero-Tavoletti MT, Okamura N, Furumoto S, Mulligan RS, Connor AR, McLean CA, Cao D, Rigopoulos
A, Cartwright GA, O’Keefe G, Gong S, Adlard PA, Barnham KJ, Rowe CC, Masters CL, Kudo Y, Cappai R, Yanai
K, Villemagne VL (2011) 18F-THK523: A novel in vivo
tau imaging ligand for Alzheimer’s disease. Brain 134,
1089-1100.
Okamura N, Furumoto S, Harada R, Furukawa K, Arai H,
Yanai K, Kudo Y (2011) Phenylquinoline derivatives for
in vivo imaging of tau pathology in Alzheimer’s disease.
Alzheimers Dement 7 (Suppl), e38.
Jones C, Nairne J (2012) Use of cyanine dyes for the detection of tau for diagnosis of early-stage tauopathies. WO
2012/068072, Prior. Nov. 19, 2010.
Watanabe H, Ono M, Kimura H, Matsumura K, Yoshimura
M, Okamoto Y, Ihara M, Takahashi R, Saji H (2012)
Synthesis and biological evaluation of novel oxindole derivatives for imaging neurofibrillary tangles in
Alzheimer’s disease. Bioorg Med Chem Lett 22, 57005703.
Bolander A, Kieser D, Voss C, Bauer S, Schon C, Burgold S, Bittner T, Holzer J, Heyny-von HR, Mall G,
Goetschy V, Czech C, Knust H, Berger R, Herms J, Hilger
I, Schmidt B (2012) Bis(arylvinyl)pyrazines, -pyrimidines,
and -pyridazines as imaging agents for tau fibrils and betaamyloid plaques in Alzheimer’s disease models. J Med
Chem 55, 9170-9180.
Jensen JR, Cisek K, Funk KE, Naphade S, Schafer KN,
Kuret J (2011) Research towards tau imaging. J Alzheimers
Dis 26(Suppl 3), 147-157.
Jensen JR, Cisek K, Honson NS, Kuret J (2011) Ligand polarizability contributes to tau fibril binding affinity.
Bioorg Med Chem 19, 5147-5154.
Boimel M, Grigoriadis N, Lourbopoulos A, Haber E,
Abramsky O, Rosenmann H (2010) Efficacy and safety of
immunization with phosphorylated tau against neurofibrillary tangles in mice. Exp Neurol 224, 472-485.
Vana L, Kanaan NM, Ugwu IC, Wuu J, Mufson EJ,
Binder LI (2011) Progression of tau pathology in cholinergic Basal forebrain neurons in mild cognitive impairment
and Alzheimer’s disease. Am J Pathol 179, 25332550.
Patterson KR, Remmers C, Fu Y, Brooker S, Kanaan
NM, Vana L, Ward S, Reyes JF, Philibert K, Glucksman
MJ, Binder LI (2011) Characterization of prefibrillar Tau
oligomers in vitro and in Alzheimer disease. J Biol Chem
286, 23063-23076.
Rosenmann H, Meiner Z, Geylis V, Abramsky O, Steinitz
M (2006) Detection of circulating antibodies against tau
protein in its unphosphorylated and in its neurofibrillary
tangles-related phosphorylated state in Alzheimer’s disease and healthy subjects. Neurosci Lett 410, 90-93.
Yen SH, Crowe A, Dickson DW (1985) Monoclonal
antibodies to Alzheimer neurofibrillary tangles. 1. Identification of polypeptides. Am J Pathol 120, 282-291.
Taniguchi T, Sumida M, Hiraoka S, Tomoo K, Kakehi T,
Minoura K, Sugiyama S, Inaka K, Ishida T, Saito N, Tanaka
C (2005) Effects of different anti-tau antibodies on tau fibrillogenesis: RTA-1 and RTA-2 counteract tau aggregation.
FEBS Lett 579, 1399-1404.
Asuni AA, Boutajangout A, Quartermain D, Sigurdsson
EM (2007) Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology
with associated functional improvements. J Neurosci 27,
9115-9129.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1598]
[1599]
[1600]
[1601]
[1602]
[1603]
[1604]
[1605]
[1606]
[1607]
[1608]
[1609]
[1610]
[1611]
[1612]
[1613]
[1614]
[1615]
[1616]
[1617]
Sigurdsson EM (2008) Immunotherapy targeting pathological tau protein in Alzheimer’s disease and related
tauopathies. J Alzheimers Dis 15, 157-168.
Zilka N, Kontsekova E, Novak M (2008) Chaperone-like
antibodies targeting misfolded tau protein: New vistas in
the immunotherapy of neurodegenerative foldopathies. J
Alzheimers Dis 15, 169-179.
Kayed R, Jackson GR (2009) Prefilament tau species as
potential targets for immunotherapy for Alzheimer disease
and related disorders. Curr Opin Immunol 21, 359-363.
Sigurdsson EM (2009) Tau-focused immunotherapy
for Alzheimer’s disease and related tauopathies. Curr
Alzheimer Res 6, 446-450.
Boutajangout A, Quartermain D, Sigurdsson EM (2010)
Immunotherapy targeting pathological tau prevents cognitive decline in a new tangle mouse model. J Neurosci 30,
16559-16566.
Kayed R (2010) Anti-tau oligomers passive vaccination
for the treatment of Alzheimer disease. Hum Vaccin 6,
931-935.
Boutajangout A, Ingadottir J, Davies P, Sigurdsson
EM (2011) Passive immunization targeting pathological
phospho-tau protein in a mouse model reduces functional
decline and clears tau aggregates from the brain. J Neurochem 118, 658-667.
Boutajangout A, Sigurdsson EM, Krishnamurthy PK
(2011) Tau as a therapeutic target for Alzheimer’s disease.
Curr Alzheimer Res 8, 666-677.
Gu J, Sigurdsson EM (2011) Immunotherapy for
tauopathies. J Mol Neurosci 45, 690-695.
Krishnamurthy PK, Deng Y, Sigurdsson EM (2011) Mechanistic studies of antibody-mediated clearance of tau
aggregates using an ex vivo brain slice model. Front Psychiatry 2, 59.
Mattson MP (2000) Emerging neuroprotective strategies
for Alzheimer’s disease: Dietary restriction, telomerase
activation, and stem cell therapy. Exp Gerontol 35, 489502.
Sugaya K, Brannen CL (2001) Stem cell strategies for
neuroreplacement therapy in Alzheimer’s disease. Med
Hypotheses 57, 697-700.
Tanne JH (2005) Activating stem cells may treat
Alzheimer’s. BMJ 330, 622.
Wang QH, Xu RX, Nagao S (2005) Transplantation
of cholinergic neural stem cells in a mouse model of
Alzheimer’s disease. Chin Med J (Engl) 118, 508-511.
Heese K, Low JW, Inoue N (2006) Nerve growth factor,
neural stem cells and Alzheimer’s disease. Neurosignals
15, 1-12.
Wang Q, Matsumoto Y, Shindo T, Miyake K, Shindo A,
Kawanishi M, Kawai N, Tamiya T, Nagao S (2006) Neural
stem cells transplantation in cortex in a mouse model of
Alzheimer’s disease. J Med Invest 53, 61-69.
Sugaya K, Alvarez A, Marutle A, Kwak YD, Choumkina E (2006) Stem cell strategies for Alzheimer’s disease
therapy. Panminerva Med 48, 87-96.
Fullwood NJ (2007) Neural stem cells, acetylcholine and
Alzheimer’s disease. Nat Chem Biol 3, 435.
Sugaya K, Kwak YD, Ohmitsu O, Marutle A, Greig NH,
Choumrina E (2007) Practical issues in stem cell therapy for Alzheimer’s disease. Curr Alzheimer Res 4, 370377.
Sugaya K, Merchant S (2008) How to approach
Alzheimer’s disease therapy using stem cell technologies.
J Alzheimers Dis 15, 241-254.
[1618]
[1619]
[1620]
[1621]
[1622]
[1623]
[1624]
[1625]
[1626]
[1627]
[1628]
[1629]
[1630]
[1631]
[1632]
[1633]
[1634]
[1635]
[1636]
109
Waldau B, Shetty AK (2008) Behavior of neural stem cells
in the Alzheimer brain. Cell Mol Life Sci 65, 2372-2384.
Lee JK, Jin HK, Bae JS (2009) Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition
and accelerate the activation of microglia in an acutely
induced Alzheimer’s disease mouse model. Neurosci Lett
450, 136-141.
Feng Z, Zhao G, Yu L (2009) Neural stem cells
and Alzheimer’s disease: Challenges and hope. Am J
Alzheimer’s Dis Other Demen 24, 52-57.
Taupin P (2009) Adult neurogenesis and the pathogenesis
of Alzheimer’s disease. Med Sci Monit 15, LE1.
Taupin P (2009) Adult neurogenesis, neural stem cells and
Alzheimer’s disease: Developments, limitations, problems
and promises. Curr Alzheimer Res 6, 461-470.
Dantuma E, Merchant S, Sugaya K (2010) Stem cells for
the treatment of neurodegenerative diseases. Stem Cell Res
Ther 1, 37.
Habisch HJ, Schmid B, von Arnim CA, Ludolph AC, Brenner R, Storch A (2010) Efficient processing of Alzheimer’s
disease amyloid-beta peptides by neuroectodermally converted mesenchymal stem cells. Stem Cells Dev 19,
629-633.
Lee HJ, Lee JK, Lee H, Shin JW, Carter JE, Sakamoto T,
Jin HK, Bae JS (2010) The therapeutic potential of human
umbilical cord blood-derived mesenchymal stem cells in
Alzheimer’s disease. Neurosci Lett 481, 30-35.
Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae
JS (2010) Intracerebral transplantation of bone marrowderived mesenchymal stem cells reduces amyloid-beta
deposition and rescues memory deficits in Alzheimer’s
disease mice by modulation of immune responses. Stem
Cells 28, 329-343.
Stellos K, Panagiota V, Sachsenmaier S, Trunk T, Straten
G, Leyhe T, Seizer P, Geisler T, Gawaz M, Laske C (2010)
Increased circulating progenitor cells in Alzheimer’s disease patients with moderate to severe dementia: Evidence
for vascular repair and tissue regeneration? J Alzheimers
Dis 19, 591-600.
Taupin P (2010) Adult neurogenesis and neural stem cells
as a model for the discovery and development of novel
drugs. Expert Opin Drug Discov 5, 921-925.
Taupin P (2010) Aging and neurogenesis, a lesion from
Alzheimer’s disease. Aging Dis 1, 158-168.
Schwarz SC, Schwarz J (2010) Translation of stem cell
therapy for neurological diseases. Transl Res 156, 155160.
Couillard-Despres S, Iglseder B, Aigner L (2011) Neurogenesis, cellular plasticity and cognition: The impact
of stem cells in the adult and aging brain–a mini-review.
Gerontology 57, 559-564.
Lunn JS, Sakowski SA, Hur J, Feldman EL (2011) Stem
cell technology for neurodegenerative diseases. Ann Neurol 70, 353-361.
Taupin P (2011) Neurogenesis, NSCs, pathogenesis and
therapies for Alzheimer’s disease. Front Biosci (Schol Ed)
3, 178-190.
Abdel-Salam OM (2011) Stem cell therapy for
Alzheimer’s disease. CNS Neurol Disord Drug Targets
10, 459-485.
Chen C, Xiao SF (2011) Induced pluripotent stem cells and
neurodegenerative diseases. Neurosci Bull 27, 107-114.
Borlongan CV (2012) Recent preclinical evidence advancing cell therapy for Alzheimer’s disease. Exp Neurol 237,
142-146.
110
[1637]
[1638]
[1639]
[1640]
[1641]
[1642]
[1643]
[1644]
[1645]
[1646]
[1647]
[1648]
[1649]
[1650]
[1651]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Rachubinski AL, Maclean KN, Evans JR, Bjugstad KB
(2012) Modulating cognitive deficits and tau accumulation
in a mouse model of aging down syndrome through neonatal implantation of neural progenitor cells. Exp Gerontol
47, 723-733.
Rachubinski AL, Crowley SK, Sladek Jr, Maclean KN,
Bjugstad KB (2012) Effects of neonatal neural progenitor cell implantation on adult neuroanatomy and cognition
in the Ts65Dn model of Down syndrome. PLoS One 7,
e36082.
Njie e, Kantorovich S, Astary GW, Green C, Zheng T,
Semple-Rowland SL, Steindler DA, Sarntinoranont M,
Streit WJ, Borchelt DR (2012) A preclinical assessment
of neural stem cells as delivery vehicles for anti-amyloid
therapeutics. PLoS One 7, e34097.
Khandekar N, Lie KH, Sachdev PS, Sidhu KS (2012)
Amyloid precursor proteins, neural differentiation of
pluripotent stem cells and its relevance to Alzheimer’s
disease. Stem Cells Dev 21, 997-1006.
Feng Z, Gao F (2012) Stem cell challenges in the treatment
of neurodegenerative disease. CNS Neurosci Ther 18, 142148.
Kitiyanant N, Kitiyanant Y, Svendsen CN, Thangnipon W
(2012) BDNF-, IGF-1- and GDNF-secreting human neural
progenitor cells rescue amyloid beta-induced toxicity in
cultured rat septal neurons. Neurochem Res 37, 143-152.
Park D, Joo SS, Kim TK, Lee SH, Kang H, Lee HJ, Lim I,
Matsuo A, Tooyama I, Kim YB, Kim SU (2012) Human
neural stem cells overexpressing choline acetyltransferase
restore cognitive function of kainic acid-induced learning
and memory deficit animals. Cell Transplant 21, 365-371.
Park D, Lee HJ, Joo SS, Bae DK, Yang G, Yang YH, Lim
I, Matsuo A, Tooyama I, Kim YB, Kim SU (2012) Human
neural stem cells over-expressing choline acetyltransferase
restore cognition in rat model of cognitive dysfunction.
Exp Neurol 234, 521-526.
Kern DS, Maclean KN, Jiang H, Synder EY, Sladek JR,
Bjugstad KB (2011) Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn down
syndrome mice. Cell Transplant 20, 371-379.
Xuan AG, Long DH, Gu HG, Yang DD, Hong LP, Leng SL
(2008) BDNF improves the effects of neural stem cells on
the rat model of Alzheimer’s disease with unilateral lesion
of fimbria-fornix. Neurosci Lett 440, 331-335.
Xuan AG, Luo M, Ji WD, Long DH (2009) Effects of
engrafted neural stem cells in Alzheimer’s disease rats.
Neurosci Lett 450, 167-171.
Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello
NA, Muller FJ, Loring JF, Yamasaki TR, Poon WW, Green
KN, LaFerla FM (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease.
Proc Natl Acad Sci U S A 106, 13594-13599.
Lee HJ, Lim IJ, Park SW, Ko YB, Kim SU (2012)
Human neural stem cells genetically modified to express
human nerve growth factor (NGF) gene restore cognition
in mouse with ibotenic acid-induced cognitive dysfunction. Cell Transplant, doi: http://dx.doi.org/10.3727/
096368912X638964
Lee HJ, Lim IJ, Lee MC, Kim SU (2010) Human neural
stem cells genetically modified to overexpress brainderived neurotrophic factor promote functional recovery
and neuroprotection in a mouse stroke model. J Neurosci
Res 88, 3282-3294.
Wu S, Sasaki A, Yoshimoto R, Kawahara Y, Manabe T,
Kataoka K, Asashima M, Yuge L (2008) Neural stem cells
[1652]
[1653]
[1654]
[1655]
[1656]
[1657]
[1658]
[1659]
[1660]
[1661]
[1662]
[1663]
[1664]
improve learning and memory in rats with Alzheimer’s
disease. Pathobiology 75, 186-194.
Wu L, Sluiter AA, Guo HF, Balesar RA, Swaab DF, Zhou
JN, Verwer RW (2008) Neural stem cells improve neuronal survival in cultured postmortem brain tissue from
aged and Alzheimer patients. J Cell Mol Med 12, 16111621.
Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T,
Yamanaka S, Okano H, Suzuki N (2011) Modeling familial
Alzheimer’s disease with induced pluripotent stem cells.
Hum Mol Genet 20, 4530-4539.
Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera
C, Hefferan MP, Van GS, Nazor KL, Boscolo FS, Carson
CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo
EH, Goldstein LS (2012) Probing sporadic and familial
Alzheimer’s disease using induced pluripotent stem cells.
Nature 482, 216-220.
Choi SH, Tanzi RE (2012) iPSCs to the rescue in
Alzheimer’s research. Cell Stem Cell 10, 235-236.
Shi Y, Kirwan P, Smith J, MacLean G, Orkin SH, Livesey
FJ (2012) A human stem cell model of early Alzheimer’s
disease pathology in Down syndrome. Sci Transl Med 4,
124ra29.
Camnasio S, Carri AD, Lombardo A, Grad I, Mariotti
C, Castucci A, Rozell B, Riso PL, Castiglioni V, Zuccato C,
Rochon C, Takashima Y, Diaferia G, Biunno I, Gellera C,
Jaconi M, Smith A, Hovatta O, Naldini L, Di DS, Feki A,
Cattaneo E (2012) The first reported generation of several
induced pluripotent stem cell lines from homozygous and
heterozygous Huntington’s disease patients demonstrates
mutation related enhanced lysosomal activity. Neurobiol
Dis 46, 41-51.
Sadan O, Bahat-Stromza M, Barhum Y, Levy YS, Pisnevsky A, Peretz H, Ilan AB, Bulvik S, Shemesh N, Krepel
D, Cohen Y, Melamed E, Offen D (2009) Protective effects
of neurotrophic factor-secreting cells in a 6-OHDA rat
model of Parkinson disease. Stem Cells Dev 18, 11791190.
Sadan O, Shemesh N, Barzilay R, Bahat-Stromza M,
Melamed E, Cohen Y, Offen D (2008) Migration of
neurotrophic factors-secreting mesenchymal stem cells
toward a quinolinic acid lesion as viewed by magnetic
resonance imaging. Stem Cells 26, 2542-2551.
McGill TJ, Cottam B, Lu B, Wang S, Girman S, Tian C,
Huhn SL, Lund RD, Capela A (2012) Transplantation of
human central nervous system stem cells - neuroprotection
in retinal degeneration. Eur J Neurosci 35, 468-477.
Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock
J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, Tuszynski MH (2012) Long-distance
growth and connectivity of neural stem cells after severe
spinal cord injury. Cell 150, 1264-1273.
Glass JD, Boulis NM, Johe K, Rutkove SB, Federici T,
Polak M, Kelly C, Feldman EL (2012) Lumbar intraspinal
injection of neural stem cells in patients with amyotrophic
lateral sclerosis: Results of a phase I trial in 12 patients.
Stem Cells 30, 1144-1151.
Borlongan CV, Skinner SJ, Geaney M, Vasconcellos AV,
Elliott RB, Emerich DF (2004) CNS grafts of rat choroid
plexus protect against cerebral ischemia in adult rats. Neuroreport 15, 1543-1547.
Borlongan CV, Skinner SJ, Geaney M, Vasconcellos AV,
Elliott RB, Emerich DF (2004) Neuroprotection by encapsulated choroid plexus in a rodent model of Huntington’s
disease. Neuroreport 15, 2521-2525.
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1665]
[1666]
[1667]
[1668]
[1669]
[1670]
[1671]
[1672]
[1673]
[1674]
[1675]
[1676]
[1677]
[1678]
[1679]
[1680]
[1681]
Brinton RD, Wang JM (2006) Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer’s
disease: Allopregnanolone as a proof of concept neurogenic agent. Curr Alzheimer Res 3, 185-190.
Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung
EJ, Thompson RF, Brinton RD (2010) Allopregnanolone
reverses neurogenic and cognitive deficits in mouse model
of Alzheimer’s disease. Proc Natl Acad Sci U S A 107,
6498-6503.
Singh C, Liu L, Wang JM, Irwin RW, Yao J, Chen S, Henry
S, Thompson RF, Brinton RD (2012) Allopregnanolone
restores hippocampal-dependent learning and memory and
neural progenitor survival in aging 3xTgAD and nonTg
mice. Neurobiol Aging 33, 1493-1506.
Tsai KJ, Tsai YC, Shen CK (2007) G-CSF rescues the
memory impairment of animal models of Alzheimer’s disease. J Exp Med 204, 1273-1280.
Zhang XZ, Li XJ, Zhang HY (2010) Valproic acid as a
promising agent to combat Alzheimer’s disease. Brain Res
Bull 81, 3-6.
Ling S, Zhou J, Rudd JA, Hu Z, Fang M (2011) The
recent updates of therapeutic approaches against abeta for
the treatment of Alzheimer’s disease. Anat Rec (Hoboken)
294, 1307-1318.
Ulloa CM, Towfigh A, Safdieh J (2009) Review of
levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset
seizures. Neuropsychiatr Dis Treat 5, 467-476.
Lyseng-Williamson KA (2011) Levetiracetam: A review
of its use in epilepsy. Drugs 71, 489-514.
Lyseng-Williamson KA (2011) Spotlight on levetiracetam
in epilepsy. CNS Drugs 25, 901-905.
Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P,
Bajjalieh SM, Matagne A, Fuks B (2004) The synaptic
vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 101, 98619866.
Lambeng N, Gillard M, Vertongen P, Fuks B, Chatelain
P (2005) Characterization of [(3)H]ucb 30889 binding to
synaptic vesicle protein 2A in the rat spinal cord. Eur J
Pharmacol 520, 70-76.
Gillard M, Chatelain P, Fuks B (2006) Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A)
in human brain and in CHO cells expressing the human
recombinant protein. Eur J Pharmacol 536, 102-108.
Dong M, Yeh F, Tepp WH, Dean C, Johnson EA, Janz
R, Chapman ER (2006) SV2 is the protein receptor for
botulinum neurotoxin A. Science 312, 592-596.
Yeh FL, Dong M, Yao J, Tepp WH, Lin G, Johnson EA,
Chapman ER (2010) SV2 mediates entry of tetanus neurotoxin into central neurons. PLoS Pathog 6, e1001207.
Vogl C, Mochida S, Wolff C, Whalley BJ, Stephens GJ
(2012) The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an
intracellular pathway. Mol Pharmacol 82, 199-208.
Angehagen M, Margineanu DG, Ben-Menachem E,
Ronnback L, Hansson E, Klitgaard H (2003) Levetiracetam reduces caffeine-induced Ca2+ transients and
epileptiform potentials in hippocampal neurons. Neuroreport 14, 471-475.
Ueda Y, Doi T, Nagatomo K, Tokumaru J, Takaki M,
Willmore LJ (2007) Effect of levetiracetam on molecular
regulation of hippocampal glutamate and GABA transporters in rats with chronic seizures induced by amygdalar
FeCl3 injection. Brain Res 1151, 55-61.
[1682]
[1683]
[1684]
[1685]
[1686]
[1687]
[1688]
[1689]
[1690]
[1691]
[1692]
[1693]
[1694]
[1695]
[1696]
[1697]
111
Noyer M, Gillard M, Matagne A, Henichart JP, Wulfert
E (1995) The novel antiepileptic drug levetiracetam (ucb
L059) appears to act via a specific binding site in CNS
membranes. Eur J Pharmacol 286, 137-146.
Loscher W, Honack D, Bloms-Funke P (1996) The novel
antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas
of rat brain and reduces neuronal activity in substantia
nigra pars reticulata. Brain Res 735, 208-216.
Sills GJ, Leach JP, Fraser CM, Forrest G, Patsalos PN,
Brodie MJ (1997) Neurochemical studies with the novel
anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol 325, 35-40.
Celikyurt IK, Ulak G, Mutlu O, Akar FY, Mulayim S,
Erden F, Komsuoglu SS (2012) Positive impact of levetiracetam on emotional learning and memory in naive
mice. Life Sci 90, 185-189.
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu GQ, Palop JJ, Mucke L
(2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an
Alzheimer’s disease model. Proc Natl Acad Sci U S A 109,
E2895-E2903.
Cho JR, Koo DL, Joo EY, Yoon SM, Ju E, Lee J, Kim
DY, Hong SB (2012) Effect of levetiracetam monotherapy
on background EEG activity and cognition in drug-naive
epilepsy patients. Clin Neurophysiol 123, 883-891.
Schiemann-Delgado J, Yang H, Loge CL, Stalvey TJ,
Jones J, Legoff D, Mintz M (2012) A long-term open-label
extension study assessing cognition and behavior, tolerability, safety, and efficacy of adjunctive levetiracetam in
children aged 4 to 16 years with partial-onset seizures.
J Child Neurol 27, 80-89.
Schulze-Bonhage A (2011) Brivaracetam for the treatment
of epilepsy. Expert Opin Pharmacother 12, 1959-1966.
Stephen LJ, Brodie MJ (2011) Pharmacotherapy of
epilepsy: Newly approved and developmental agents. CNS
Drugs 25, 89-107.
Gillard M, Fuks B, Leclercq K, Matagne A (2011) Binding
characteristics of brivaracetam, a selective, high affinity
SV2A ligand in rat, mouse and human brain: Relationship
to anti-convulsant properties. Eur J Pharmacol 664, 36-44.
Zona C, Pieri M, Carunchio I, Curcio L, Klitgaard H,
Margineanu DG (2010) Brivaracetam (ucb 34714) inhibits
Na(+) current in rat cortical neurons in culture. Epilepsy
Res 88, 46-54.
Detrait ER, Leclercq K, Loscher W, Potschka H,
Niespodziany I, Hanon E, Kaminski RM, Matagne A,
Lamberty Y (2010) Brivaracetam does not alter spatial
learning and memory in both normal and amygdalakindled rats. Epilepsy Res 91, 74-83.
Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW
(2011) Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam. Epilepsia 52, 264-272.
Selkoe DJ (2012) Preventing Alzheimer’s disease. Science
337, 1488-1492.
Froestl W, Muhs A, Pfeifer A (2012) Cognitive Enhancers
(Nootropics). Part 2: Drugs Interacting with Enzymes. J
Alzheimers Dis 33, 547-658.
Morimoto K, Horio J, Satoh H, Sue L, Beach T, Arita
S, Tooyama I, Konishi Y (2011) Expression profiles
of cytokines in the brains of Alzheimer’s disease (AD)
patients compared to the brains of non-demented patients
with and without increasing AD pathology. J Alzheimers
Dis 25, 59-76.
112
[1698]
[1699]
[1700]
[1701]
[1702]
[1703]
[1704]
[1705]
[1706]
[1707]
[1708]
[1709]
[1710]
[1711]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
Zhou W, Zhong GF, Roa Xr, Xie H, Zeng SG, Chi
TY, Zou LB, Wu DH, Hu WH (2012) Identification of
aminopyridazine-derived antineuroinflammatory agents
effective in an Alzheimer’s mouse model. ACS Med Chem
Lett, dx.doi.org/10.1021/ml3001769Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE,
Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG,
Peters O, Winter Y, Becher B, Heppner FL (2012)
Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s
disease-like pathology and cognitive decline. Nat Med,
doi: 10.1038/nm.2965Chan D (2012) American Chemical Society - 33rd
National Medicinal Chemistry Symposium (NMCS).
Drugs of the Future 37, 599-603.
Thompson AD, Scaglione KM, Prensner J, Gillies AT,
Chinnaiyan A, Paulson HL, Jinwal UK, Dickey CA, Gestwicki JE (2012) Analysis of the tau-associated proteome
reveals that exchange of hsp70 for hsp90 is involved in tau
degradation. ACS Chem Biol 7, 1677-1686.
Berridge MJ (2013) Dysregulation of neural calcium
signaling in Alzheimer disease, bipolar disorder and
schizophrenia. Prion 7 [Epub ahead of print].
Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB,
Edison P, Hagan JJ, Holmes C, Jones E, Katona C, Kearns
I, Kehoe P, Mudher A, Passmore A, Shepherd N, Walsh
F, Ballard C (2012) Drug repositioning for Alzheimer’s
disease. Nat Rev Drug Discov 11, 833-846.
Gholamipour-Badie H, Naderi N, Khodagholi F,
Shaerzadeh F, Motamedi F (2013) L-type calcium
channel blockade alleviates molecular and reversal spatial
learning and memory alterations induced by entorhinal
amyloid pathology in rats. Behav Brain Res 237,
190-199.
Mufson EJ, He B, Nadeem M, Perez SE, Counts SE,
Leurgans S, Fritz J, Lah J, Ginsberg SD, Wuu J, Scheff
SW (2012) Hippocampal ProNGF Signaling Pathways and
beta-Amyloid Levels in Mild Cognitive Impairment and
Alzheimer Disease. J Neuropathol Exp Neurol 71, 10181029.
Bendheim PE, Poeggeler B, Neria E, Ziv V, Pappolla MA,
Chain DG (2002) Development of indole-3-propionic acid
(OXIGON) for Alzheimer’s disease. J Mol Neurosci 19,
213-217.
Bush AI (2012) The Metal Theory of Alzheimer’s Disease.
J Alzheimers Dis, doi: 10.3233/JAD-2012-129011Wei G, Yunbo C, Chen DF, Lai XP, Liu DH, Deng
RD, Zhou JH, Zhang SX, Li YW, Li H, Liu LF
(2012) beta-Asarone Inhibits Neuronal Apoptosis via the
CaMKII/CREB/Bcl-2 Signaling Pathway in an in vitro
Model and AbetaPP/PS1 Mice. J Alzheimers Dis, doi:
10.3233/JAD-2012-120865Brunhofer G, Fallarero A, Karlsson D, Batista-Gonzalez
A, Shinde P, Gopi MC, Vuorela P (2012) Exploration
of natural compounds as sources of new bifunctional
scaffolds targeting cholinesterases and beta amyloid aggregation: The case of chelerythrine. Bioorg Med Chem 20,
6669-6679.
Zhao X, Zou Y, Xu H, Fan L, Guo H, Li X, Li G, Zhang X,
Dong M (2012) Gastrodin protect primary cultured rat hippocampal neurons against amyloid-beta peptide-induced
neurotoxicity via ERK1/2-Nrf2 pathway. Brain Res 1482,
13-21.
Zhu X, Ye L, Ge H, Chen L, Jiang N, Qian L, Li L, Liu R,
Ji S, Zhang S, Jin J, Guan D, Fang W, Tan R, Xu Y (2012)
Hopeahainol A attenuates memory deficits by targeting
[1712]
[1713]
[1714]
[1715]
[1716]
[1717]
[1718]
[1719]
[1720]
[1721]
[1722]
[1723]
[1724]
[1725]
beta-amyloid in APP/PS1 transgenic mice. Aging Cell, doi:
10.1111/acel.12022Zou Y, Hong B, Fan L, Zhou L, Liu Y, Wu Q,
Zhang X, Dong M (2012) Protective effect of puerarin
against beta-amyloid-induced oxidative stress in neuronal cultures from rat hippocampus: involvement of
the GSK-3beta/Nrf2 signaling pathway. Free Radic Res,
doi:10.3109/10715762.2012.742518Ho L, Ferruzzi MG, Janle EM, Wang J, Gong B, Chen
TY, Lobo J, Cooper B, Wu QL, Talcott ST, Percival SS,
Simon JE, Pasinetti GM (2012) Identification of braintargeted bioactive dietary quercetin-3-O-glucuronide as a
novel intervention for Alzheimer’s disease. FASEB J, doi:
10.1096/fj.12-212118McCracken C, Hudson P, Ellis R, McCaddon A (2006)
Methylmalonic acid and cognitive function in the Medical
Research Council Cognitive Function and Ageing Study.
Am J Clin Nutr 84, 1406-1411.
Moore E, Mander A, Ames D, Carne R, Sanders K, Watters
D (2012) Cognitive impairment and vitamin B12: a review.
Int Psychogeriatr, 1-16.
Llewellyn DJ, Langa KM, Lang IA (2009) Serum
25-hydroxyvitamin D concentration and cognitive impairment. J Geriatr Psychiatry Neurol 22, 188-195.
Llewellyn DJ, Lang IA, Langa KM, Muniz-Terrera G,
Phillips CL, Cherubini A, Ferrucci L, Melzer D (2010)
Vitamin D and risk of cognitive decline in elderly persons.
Arch Intern Med 170, 1135-1141.
Llewellyn DJ, Lang IA, Langa KM, Melzer D (2011)
Vitamin D and cognitive impairment in the elderly
U.S. population. J Gerontol A Biol Sci Med Sci 66,
59-65.
Wang L, Ankati H, Akubathini SK, Balderamos M, Storey
CA, Patel AV, Price V, Kretzschmar D, Biehl ER, D’Mello
SR (2010) Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo
models of neurodegeneration. J Neurosci Res 88, 19701984.
Hampel H (2012) Amyloid-beta and Cognition in
Aging and Alzheimer’s Disease: Molecular and Neurophysiological Mechanisms. J Alzheimers Dis, doi:
10.3233/JAD-2012-129003Lim YY, Pietrzak RH, Ellis KA, Jaeger J, Harrington K,
Ashwood T, Szoeke C, Martins RN, Bush AI, Masters
CL, Rowe CC, Villemagne VL, Ames D, Darby D, Maruff
P (2012) Rapid Decline in Episodic Memory in Healthy
Older Adults with High Amyloid-beta. J Alzheimers Dis,
doi: 10.3233/JAD-2012-121516Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, Martins RN, Masters CL, Rowe C, Savage
G, Szoeke C, Villemagne VL, Maruff P (2012) Stronger
effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. Neurology 79, 16451652.
Lim YY, Ellis KA, Harrington K, Pietrzak RH, Gale
J, Ames D, Bush AI, Darby D, Martins RN, Masters
CL, Rowe CC, Savage G, Szoeke C, Villemagne VL,
Maruff P (2012) Cognitive Decline in Adults with Amnestic Mild Cognitive Impairment and High Amyloid-beta:
Prodromal Alzheimer’s Disease? J Alzheimers Dis, doi:
10.3233/JAD-121771Said G, Grippon S, Kirkpatrick P (2012) Tafamidis. Nat
Rev Drug Discov 11, 185-186.
Echeverria V, Zeitlin R, Burgess S, Patel S, Barman A,
Thakur G, Mamcarz M, Wang L, Sattelle DB, Kirschner
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
[1726]
[1727]
[1728]
[1729]
[1730]
[1731]
[1732]
[1733]
[1734]
[1735]
[1736]
[1737]
[1738]
DA, Mori T, Leblanc RM, Prabhakar R, Arendash
GW (2011) Cotinine reduces amyloid-beta aggregation
and improves memory in Alzheimer’s disease mice. J
Alzheimers Dis 24, 817-835.
Ghosh S (2012) Alzheimer’s Association International
Conference. Drugs of the Future 37, 663-670.
O’Hare E, Scopes DI, Kim EM, Palmer P, Jones
M, Whyment AD, Spanswick D, Amijee H, Nerou
E, McMahon B, Treherne JM, Jeggo R (2012)
Orally bioavailable small molecule drug protects memory in Alzheimer’s disease models. Neurobiol Aging,
doi:10.1016/j.neurobiolaging.2012.10.016McKoy AF, Chen J, Schupbach T, Hecht MH (2012) A
Novel Inhibitor of Amyloid beta (Abeta) Peptide Aggregation: From high throughput screening to efficacy in an
animal model of Alzheimer disease 1. J Biol Chem 287,
38992-39000.
Amijee H, Bate C, Williams A, Virdee J, Jeggo R, Spanswick D, Scopes DI, Treherne JM, Mazzitelli S, Chawner
R, Eyers CE, Doig AJ (2012) The N-Methylated Peptide SEN304 Powerfully Inhibits Abeta(1-42) Toxicity
by Perturbing Oligomer Formation. Biochemistry, doi:
10.1021/bi300415vMathis CA, Mason NS, Lopresti BJ, Klunk WE (2012)
Development of Positron Emission Tomography betaAmyloid Plaque Imaging Agents. Semin Nucl Med 42,
423-432.
Landau SM, Breault C, Joshi AD, Pontecorvo M, Mathis
CA, Jagust WJ, Mintun MA (2012) Amyloid-beta Imaging
with Pittsburgh Compound B and Florbetapir: Comparing
Radiotracers and Quantification Methods. J Nucl Med, doi:
10.2967/jnumed.112.109009Handen BL, Cohen AD, Channamalappa U, Bulova P,
Cannon SA, Cohen WI, Mathis CA, Price JC, Klunk
WE (2012) Imaging brain amyloid in nondemented young
adults with Down syndrome using Pittsburgh compound
B. Alzheimers Dement 8, 496-501.
Doraiswamy PM, Sperling RA, Coleman RE, Johnson KA,
Reiman EM, Davis MD, Grundman M, Sabbagh MN, Sadowsky CH, Fleisher AS, Carpenter A, Clark CM, Joshi
AD, Mintun MA, Skovronsky DM, Pontecorvo MJ (2012)
Amyloid-beta assessed by florbetapir F 18 PET and 18month cognitive decline: A multicenter study. Neurology
79, 1636-1644.
Furst AJ, Kerchner GA (2012) From Alois to Amyvid:
Seeing Alzheimer disease. Neurology 79, 1628-1629.
Poisnel G, Dhilly M, Moustie O, Delamare J, Abbas A,
Guilloteau D, Barre L (2012) PET imaging with [18F]AV45 in an APP/PS1-21 murine model of amyloid plaque
deposition. Neurobiol Aging 33, 2561-2571.
Fodero-Tavoletti MT, Brockschnieder D, Villemagne VL,
Martin L, Connor AR, Thiele A, Berndt M, McLean CA,
Krause S, Rowe CC, Masters CL, Dinkelborg L, Dyrks
T, Cappai R (2012) In vitro characterization of [(18)F]florbetaben, an Abeta imaging radiotracer. Nucl Med Biol
39, 1042-1048.
Swahn BM, Sandell J, Pyring D, Bergh M, Jeppsson F,
Jureus A, Neelissen J, Johnstrom P, Schou M, Svensson
S (2012) Synthesis and evaluation of pyridylbenzofuran,
pyridylbenzothiazole and pyridylbenzoxazole derivatives
as (1)(8)F-PET imaging agents for beta-amyloid plaques.
Bioorg Med Chem Lett 22, 4332-4337.
Swahn BM, Wensbo D, Sandell J, Sohn D, Slivo C, Pyring
D, Malmstrom J, Arzel E, Vallin M, Bergh M, Jeppsson F,
Johnson AE, Jureus A, Neelissen J, Svensson S (2010)
[1739]
[1740]
[1741]
[1742]
[1743]
[1744]
[1745]
[1746]
[1747]
[1748]
[1749]
[1750]
[1751]
[1752]
[1753]
113
Synthesis and evaluation of 2-pyridylbenzothiazole, 2pyridylbenzoxazole and 2-pyridylbenzofuran derivatives
as 11C-PET imaging agents for beta-amyloid plaques.
Bioorg Med Chem Lett 20, 1976-1980.
Nelson LD, Siddarth P, Kepe V, Scheibel KE, Huang SC,
Barrio JR, Small GW (2011) Positron emission tomography of brain beta-amyloid and tau levels in adults with
Down syndrome. Arch Neurol 68, 768-774.
Shin J, Kepe V, Barrio JR, Small GW (2011) The merits of FDDNP-PET imaging in Alzheimer’s disease. J
Alzheimers Dis 26(Suppl 3), 135-145.
Montanes M, Casabona D, Sarasa L, Pesini P, Sarasa M
(2012) Prevention of Amyloid-beta Fibril Formation Using
Antibodies Against the C-terminal Region of Amyloidbeta1-40 and Amyloid-beta1-42. J Alzheimers Dis, doi:
10.3233/JAD-120850Bard F, Fox M, Friedrich S, Seubert P, Schenk D, Kinney GG, Yednock T (2012) Sustained levels of antibodies
against Abeta in amyloid-rich regions of the CNS following intravenous dosing in human APP transgenic mice.
Exp Neurol 238, 38-43.
Solomon B (2007) Intravenous immunoglobulin and
Alzheimer’s disease immunotherapy. Curr Opin Mol Ther
9, 79-85.
Robert R, Wark KL (2012) Engineered antibody
approaches for Alzheimer’s disease immunotherapy. Arch
Biochem Biophys 526, 132-138.
Yu G, Li Y, Tian Q, Liu R, Wang Q, Wang JZ, Wang X
(2011) Berberine attenuates calyculin A-induced cytotoxicity and Tau hyperphosphorylation in HEK293 cells. J
Alzheimers Dis 24, 525-535.
Peng Y, Hu Y, Xu S, Li P, Li J, Lu L, Yang H, Feng
N, Wang L, Wang X (2012) L-3-n-butylphthalide reduces
tau phosphorylation and improves cognitive deficits in
AbetaPP/PS1-Alzheimer’s transgenic mice. J Alzheimers
Dis 29, 379-391.
Tolstykh T, Lee J, Vafai S, Stock JB (2000) Carboxyl
methylation regulates phosphoprotein phosphatase 2A
by controlling the association of regulatory B subunits.
EMBO J 19, 5682-5691.
Vafai SB, Stock JB (2002) Protein phosphatase 2A methylation: A link between elevated plasma homocysteine and
Alzheimer’s Disease. FEBS Lett 518, 1-4.
Xing Y, Li Z, Chen Y, Stock JB, Jeffrey PD, Shi Y (2008)
Structural mechanism of demethylation and inactivation
of protein phosphatase 2A. Cell 133, 154-163.
Butler KV, Kalin J, Brochier C, Vistoli G, Langley B,
Kozikowski AP (2010) Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor,
tubastatin A. J Am Chem Soc 132, 10842-10846.
Benner L, Kalin JH, Kozikowski A, Gordon MN, Morgan D, Selenica MB (2012) Selective HDAC6 inhibition
decreases tau levels and improves memory deficits in the
rtg4510 mouse model. Society for Neuroscience, New
Orleans, Poster 150.04-Sunday, November 14, 2012.
Okamura N, Suemoto T, Furumoto S, Suzuki M, Shimadzu H, Akatsu H, Yamamoto T, Fujiwara H, Nemoto
M, Maruyama M, Arai H, Yanai K, Sawada T, Kudo
Y (2005) Quinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in
Alzheimer’s disease. J Neurosci 25, 10857-10862.
Gu J, Anumala UR, Lo MF, Kramer T, Heyny von
HR, Holzer J, Goetschy-Meyer V, Mall G, Hilger
I, Czech C, Schmidt B (2012) 2-Styrylindolium
based fluorescent probes visualize neurofibrillary tan-
114
[1754]
[1755]
[1756]
[1757]
[1758]
[1759]
W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 3: Drugs Interacting with Targets other than Receptors or Enzymes
gles in Alzheimer’s disease. Bioorg Med Chem Lett,
http://dx.doi.org/10.1016/j.bmcl.2012.09.109Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims
H, Buckner N, Hanmer J, Davies P, O’Neill MJ, Hutton
ML, Citron M (2011) Passive immunization with antiTau antibodies in two transgenic models: reduction of Tau
pathology and delay of disease progression. J Biol Chem
286, 34457-34467.
Shih HH, Tu C, Cao W, Klein A, Ramsay R, Fennell BJ,
Lambert M, Ni SD, Autin B, Kouranova E, Laxmanan
S, Braithwaite S, Wu L, it-Zahra M, Milici AJ, Dumin
JA, Lavallie ER, Arai M, Corcoran C, Paulsen JE, Gill D,
Cunningham O, Bard J, Mosyak L, Finlay WJ (2012) An
ultra-specific avian antibody to phosphorylated tau reveals
a unique mechanism for phosphoepitope recognition. J
Biol Chem, doi: 10.1074/jbc.M112.415935Wang W, Fan L, Xu D, Wen Z, Yu R, Ma Q (2012)
Immunotherapy for Alzheimer’s disease. Acta Biochim
Biophys Sin (Shanghai) 44, 807-814.
Young JE, Goldstein LS (2012) Alzheimer’s disease in a
dish: promises and challenges of human stem cell models.
Hum Mol Genet 21, R82-R89.
Grskovic M, Javaherian A, Strulovici B, Daley GQ (2011)
Induced pluripotent stem cells–opportunities for disease
modelling and drug discovery. Nat Rev Drug Discov 10,
915-929.
Uchida N, Chen K, Dohse M, Hansen KD, Dean J, Buser
JR, Riddle A, Beardsley DJ, Wan Y, Gong X, Nguyen T,
Cummings BJ, Anderson AJ, Tamaki SJ, Tsukamoto A,
Weissman IL, Matsumoto SG, Sherman LS, Kroenke CD,
[1760]
[1761]
[1762]
[1763]
[1764]
[1765]
[1766]
Back SA (2012) Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci
Transl Med 4, 155ra136Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci
M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, Perry
R, Farrell J, Jeremy RJ, Ulman M, Huhn SL, Barkovich
AJ, Rowitch DH (2012) Neural stem cell engraftment
and myelination in the human brain. Sci Transl Med 4,
155ra137Moreira PI, Santos RX, Zhu X, Lee HG, Smith MA,
Casadesus G, Perry G (2010) Autophagy in Alzheimer’s
disease. Expert Rev Neurother 10, 1209-1218.
Barnett A, Brewer GJ (2011) Autophagy in aging
and Alzheimer’s disease: Pathologic or protective? J
Alzheimers Dis 25, 385-394.
Schaeffer V, Goedert M (2012) Stimulation of autophagy
is neuroprotective in a mouse model of human tauopathy.
Autophagy 8, http://dx.doi.org/10.4161/auto.21488Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT,
Goedert M (2012) Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy.
Brain 135, 2169-2177.
Brown JR, Crawford BE, Esko JD (2007) Glycan antagonists and inhibitors: A fount for drug discovery. Crit Rev
Biochem Mol Biol 42, 481-515.
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR,
Stark CE, Yassa MA, Bassett SS, Shelton AL, Gallagher M
(2012) Reduction of hippocampal hyperactivity improves
cognition in amnestic mild cognitive impairment. Neuron
74, 467-474.