Download Neurodegenerative Pathways in Parkinson`s Disease: Therapeutical

Current Drug Targets - CNS & Neurological Disorders, 2005, 4, 405-419
405
Neurodegenerative Pathways in Parkinson’s Disease: Therapeutical
Strategies
S.M. Cardoso +, P.I. Moreira +, P. Agostinho, C. Pereira and C.R. Oliveira*
Center for Neuroscience and Cell Biology and Institute of Biochemistry, Faculty of Medicine of Coimbra,
University of Coimbra, 3004-504 Coimbra, Portugal
Abstract: Parkinson’s disease (PD), considered one of the major neurological disorders, is characterized by the
loss of dopaminergic neurons in the pars compacta of the substantia nigra and by the presence of intraneuronal
cytoplasmic inclusions called Lewy bodies. The causes for degeneration of PD neurons remain unclear,
however, recent findings contributed to clarify this issue. This review will discuss the current understanding of
the mechanisms underlying Parkinson’s disease pathogenesis, focusing on the current and potential
therapeutic strategies for human treatment.
Keywords: α-synuclein, neuronal circuits, oxidative stress, mitochondria, proteasome, neuroinflammation, cell death,
therapeutics.
ETIOPATHOGENESIS OF PARKINSON’S DISEASE
Parkinson’s disease (PD) is the most common
progressive neurodegenerative movement disorder with a
prevalence of about 2% in individuals older than 65 years of
age. However, the disease can also manifest earlier in life,
before 40 to 50 years, referred as early onset PD [1]. It is
characterized clinically by tremor, rigidity, bradykinesia and
postural instability, and non-motor symptoms such as
cognitive and mood impairment, and autonomic dysfunction
can also be observed. Pathologically, PD is characterized by
selective neuronal loss of dopaminergic neurons in the
substantia nigra pars compacta (SNc), which leads to a
drastic depletion of dopamine (DA) levels in the striatum, to
which these neurons project [2]. Although the course of the
disease is unknown, the leading hypothesis for the death of
specific groups of neurons establishes that alterations in
protein aggregation, proteasomal system impairment,
mitochondrial dysfunction and oxidative stress are the major
events that act synergistically causing this devastating
disease.
Neuropathological Hallmarks in PD
The most prominent histopathological hallmarks of PD
are the intracellular accumulation of insoluble fibrous
material, named Lewy bodies (LBs), found in the cytoplasm
of neurons, often near the nucleus, and dystrophic neurites
(Lewy neurites) found in axons and dendrites. LBs are
intracytoplasmic aggregates of several proteins, including αsynuclein, ubiquitin, synphilin-1, 14-3-3 proteins, tubulin
and other cytoskeletal proteins.
α-Synuclein can polymerize into ~ 10-nm fibrils in vitro
and is the primary structural component of LBs [2, 3, 4]. In
PD, these intracytoplasmic inclusions are distributed in the
*Address correspondence to the author at the Center for Neuroscience
and Cell Biology and Institute of Biochemistry, Faculty of Medicine of
Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; Tel: 351239-820190; Fax: 351-239-822776; E-mail: [email protected]
substantia nigra, locus coeruleus, medulla, olfactory bulb,
and to a lesser extent in various cortical areas [5].
Familiar Forms of PD
Despite the overall rarity of the familiar forms of PD
(<10% of the cases), the identification of single genes linked
to the disease has yielded crucial insights into possible
mechanisms of PD pathogenesis [for review see: 6, 7]. A
role for α-synuclein in PD was fueled by the identification
of a missense mutation in the α-synuclein gene as a cause of
autosomal dominantly inherited PD [8]. Two mutations
were identified, an Ala53Thr (A53T) mutation resulting
from a G to A transition at position 209, and an Ala30Pro
(A30P) mutation resulting from a G to C transition at
position 88 [8, 9]. A genomic duplication or triplication of
wild-type (wt) α-synuclein is the cause of the disease in
some cases of familiar PD [10, 11]. Mutations in DJ-1 gene
cause autosomal recessive PD. The large homozygous
deletion of DJ-1 leads to protein loss, whereas a Lys166Pro
point mutation destabilizes the protein. Recent structural
studies indicate that DJ-1, which participates in the
oxidative stress response by scavenging H2O2, may have
similarities to the bacterial heat shock protein 31 (HSP31)
homologs, suggesting that it may function as a chaperon to
alleviate protein misfolding by interacting with earlyunfolding intermediates [12, 13, 14]. Another familiar PD
mutation affects ubiquitin carboxyl-terminal hydrolase-1
(UCHL1), a component of the cell ubiquitin-proteasome
system (UPS) that degrades damaged proteins; UCHL1 has
both hydrolase and ubiquitin ligase activities [15]. A more
common causative mutation that involves the UPS affects an
ubiquitin E3 ligase called parkin [16]. The Arg42Pro
mutation in parkin causes autosomal recessive juvenile PD,
possibly impairing parkin proteasomal interaction [17]. The
Arg256Cys and Arg275Trp mutations cause altered protein
localization and increased aggregation [18]. These mutations
confer a loss-of-function of parkin’s E3 ligase activity;
therefore, a great importance has been placed on the protein
substrates of parkin. Parkin acts together with α-synuclein
interacting protein synphilin-1, promoting the formation of
+The authors contributed equally to this review.
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LBs. Alternatively, parkin may interrelate with a minor Olinked glycosylated form of α-synuclein [19], and it has
been hypothesized that parkin may act specifically on
aberrant α-synuclein deposits (protofibrils/fibrils or
oligomers). It was postulated that parkin rescues impaired
proteasome function, thus preventing the toxic effects of
mutant α-synuclein [20, 21]. Recently, a new familiar form
of PD was identified, characterized by mutations in a
putative mitochondrial protein kinase called PTEN-induced
kinase 1 (PINK1) [22]. The missense mutation Gly309Asp
is located in its ADP binding site, probably interfering with
ADP binding and kinase activity, whereas the Trp437STOP
mutation causes truncation of PINK1 in the helical kinase
domain, probably destroying the enzyme. PINK1 contains a
highly conserved kinase domain similar to serine/threonine
kinases of the Ca2+ -calmodulin family, which has been
hypothesized to phosphorylate mitochondrial proteins in
response to cellular stress, protecting against mitochondrial
dysfunction [22].
PARKINSON’S DISEASE, A MISFOLDED PROTEIN
DISORDER
-Synuclein Protein
α-Synuclein mutations are autosomal dominant and
represent a toxic gain-of-function mutation, resulting in
abnormal protein accumulations [23, 24]. Even though
mutations in α-synuclein are very rare causes of hereditary
PD, its apparent role as the major structural feature of the
LBs has placed α-synuclein at the center stage in PD
pathophysiology [for review see: 25]. α-Synuclein is a 140amino acid protein whose cellular function is still unknown.
This protein is normally unfolded, revealing little threedimensional structure. The α-synuclein non-amyloidogenic
component (NAC) domain appears to be responsible for its
aggregating properties and can form oligomers of β-pleated
sheets called protofibrils that can additionally form fibrils
found in LBs and neuritis [26]. Moreover, it has been
discussed that protofibrils are toxic, and cells that contain
LBs represent those that have managed to evade the toxic
mechanisms involved in PD [27]. Several lines of evidence
suggest that α-synuclein may play a role in vesicular
function at synaptic level, since it is associated to vesicles
and co-localizes with synaptophysin in presynaptic terminals
[28]. Ostrerova and co-workers [29] proposed that αsynuclein could have a chaperone-like function since it has
homology with 14-3-3 proteins. α-Synuclein appears to be
associated with membrane compartments in cultured cells
and brain tissue through interactions with acidic head groups
of phospholipids [30]. Membrane-bound α-synuclein may
play an important role in fibril formation [30, 31]. The
molecular pathways of α-synuclein-mediated toxicity are
unknown, but increased oxidative stress, mitochondrial
injury and altered cellular transport have been proposed [7].
Fibrillization and aggregation of α-synuclein may be
central in PD neuronal demise. The first evidence comes
from the mutated α-synuclein familiar forms of PD where
α-synuclein has an increased tendency to aggregate as
compared to wt. There are several theories for in vivo αsynuclein aggregation in sporadic PD. Foremost
mitochondrial dysfunction theory since complex I inhibition
was shown to increase α-synuclein accumulation [32-36]
Oliveira et al.
(see Mitochondrial dysfunction section). Oxidative stress
also seems to participate in this process [37], given that free
radicals can induce α-synuclein aggregation (see Oxidative
stress section). Proteasome dysfunction might also have a
role in α-synuclein accumulation and aggregation [39, 40],
since proteasome inhibitors induce α-synuclein aggregation
(see Impairment in the proteasomal system section) (Fig. 1).
Moreover, Giasson and colleagues [38] reported that αsynuclein induces tau fibrillization in vivo and in vitro, and
both proteins synergistically promote the polymerization of
each other into fibrillar intracellular deposits. Both proteins
can be phosphorylated, which facilitates their conversion
into fibrils. The aggregation of tau and α-synuclein as
fibrillar deposits can lead to their sequestration, thus putting
them off from performing their functions [41].
Transgenic Models
To further elucidate the in vivo function of α-synuclein,
several transgenic mice were developed. Knockout of the αsynuclein gene in mice resulted in a reduced level of
dopamine in the striatum [42], reduction of the reserve pool
of synaptic vesicles in the hippocampus and
electrophysiological abnormalities, suggesting a role for αsynuclein in presynaptic regulation [43]. Dauer and coworkers [44] also generated α-synuclein null mice that were
resistant to acute chronic 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) treatment. Since 1-methyl-4phenylpyridinium (MPP+ ), a mitochondrial complex I
inhibitor, interacts with a variety of elements in the synaptic
machinery, like the dopamine transporter, the vesicular
monoamine transporter and vesicles, this outcome may
reflect a participation of α-synuclein in vesicular function.
An additional α-synuclein knockout mouse was generated
by Schluter and collaborators [45] that had only a partial
protection from MPTP-induced striatal dopamine loss.
Overexpression of wt human α-synuclein in mice
resulted in loss of dopaminergic terminals, intranuclear and
cytoplasmic ubiquitin inclusions in the substantia nigra,
hippocampus, and cortex, and in motor deficit [46].
Expression of the A53T human α-synuclein in mice induced
an early and dramatic decline of motor function [47].
Although the neuropathological assessment revealed the
presence of α-synuclein, ubiquitin-positive inclusions and
fibrillation of the microtubule-associated protein, tau, no
modification in the nigrostriatal system was observed [47,
48].
In most of the transgenic models, the development of
fibrillar α-synuclein inclusions seems to be associated with
neurodegeneration. However, in one strain of transgenic
mice, the parkinson’s phenotype appears to be associated
with non fibrillar α-synuclein inclusions [46], raising the
possibility that protofibrils may also have a role on the
neurodegenerative pathway [49]. In contrast, Lee and
colleagues [50] reported that A30P protofibrillogenic αsynuclein transgenic mice did not show neurodegeneration.
Synaptic Dysfunction
The role of α-synuclein in synaptic function has been
described for its soluble form. Soluble α-synuclein is able
to decrease the activity of tyrosine hydroxylase (TH), thus
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Fig. (1). Representative diagram exemplifying the neurotoxic mechanisms underlying Parkinson’s disease. Mutations of five nuclear
genes are known to cause PD; they encode α-synuclein, UCHL1, parkin, DJ-1 and PINK1. Alteration in the normal function of these
proteins may induce proteasome dysfunction, mitochondrial impairment, oxidative stress and synaptic dysfunction. Such
mechanisms contribute to PD pathogenesis through induction of selective loss of nigrostriatal dopaminergic neurons. These
degenerating neurons may trigger microglia activation, which by the release of pro-inflammatory and neurotoxic factors exacerbates
the neurodegenerative process. UCHL1, ubiquitin carboxyl-terminal hydrolase-1; Parkin, ubiquitin E3 ligase; PINK1, PTEN-induced
kinase 1; UPS, ubiquitin-proteasome system; NO., nitric oxide.
modulating the amount of dopamine that is synthesized into
the nerve terminal [51]. It can regulate the availability of
synaptic vesicles and the reuptake of dopamine by the
vesicular monoamine transporter 2 (VMAT2), therefore
controlling catecholamine storage at nerve terminals [52,
53], and can reduce the maximal reuptake of dopamine from
the extracellular synapse by dopamine transporter (DAT) [54,
55], modulating the time that dopamine remains in the
synaptic cleft.
tubulin, tau, MAP2 and synphilin-1 [56]. In addition, the
A53T mutant showed a decrease of dopamine release and
vesicular dopamine storage through down regulation of
VMAT2, probably due to a depletion of vesicular dopamine
leading to its cytosolic accumulation [57]. Moreover, a
decrease in VMAT2 labeling in patients with idiopathic PD
has been described [59]. The toxic forms of α-synuclein can
permeabilize vesicles, causing the leakage of small
molecules, such as dopamine, to the cytosol [52].
An alteration of α-synuclein synaptic function occurs
upon its oligomerization into soluble protofibrils, and
further to insoluble fibrils that may contribute to synaptic
dysfunction.
In the terminals of dopamine-synthesizing neurons, αsynuclein modulates the functional activity of DAT. This
transporter is responsible for the synaptic dopamine
concentration and consequently, for the maintenance of
dopaminergic neurotransmission. Wersinger and colleagues
[54, 55] showed that α-synuclein markedly decreased DAT
activity. Moreover, the same authors showed that αsynuclein interacted directly with DAT, modulating
dopamine reuptake into the cytosol. Furthermore, A53T
mutant was unable to modulate DAT function [55]. This
shut down in DAT regulation could be responsible for the
increase of dopamine in the cytosol, leading to dopamineinduced neurotoxicity.
Dopamine synthesis depends upon the conversion of
tyrosine into L-dopa (levodihydroxyphenylalanine) by
phosphorylated TH. The reduced availability of cytosolic αsynuclein, due to an increased aggregation state, might be
responsible for the deleterious overproduction of cytosolic
dopamine, generating an increase in highly reactive species
such as quinones and superoxide free radicals [56].
α-Synuclein also plays a role in synaptic plasticity, since
α-synuclein depleted cells exhibit a decreased expression in
the levels of synapsin, an essential protein for synaptic
vesicle recycling [43, 57]. Furthermore, α-synuclein inhibits
the activity of phospholipase D2 (PLD2), which is involved
in the building of vesicle from donor membranes and
consequently, also controls vesicle formation and synaptic
vesicles recycling [58]. It has been suggested that αsynuclein interferes with axonal transport of synaptic
vesicles, by interaction with cytoskeleton proteins such as
CELLULAR AND MOLECULAR PATHWAYS IN
PARKINSON’S DISEASE
Deregulation of Neurotransmission
The degeneration of dopaminergic neurons is combined
with different degrees of alteration in GABAergic,
glutamatergic, serotoninergic and norepinephrinergic systems
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[60, 61], leading to a variety of motor and non-motor
defects. Indeed, the loss of dopaminergic neurons
compromises the tonic inhibitory control of DA on
acetylcholine (ACh) release, leading to hyperactivity of
striatum. On the other hand, the DA deficiency causes
opposite effects on subsets of striatal projecting GABAergic
neurons that express different subtypes of DA receptors,
whereas the neurons that mostly express D2 receptors
become overactive and the D1-containing neurons become
hypoactive. The increased activity of GABAergic D2contaning neurons causes a more profound inhibition of
globus pallidus pars externa (GPe) activity that in turn can
disinhibit subthalamic nucleus (STN). The overactivation of
STN, caused by nigral dopaminergic neurons loss, leads to
an excessive inhibitory output from the globus pallidus pars
interna (GPi) and substantia nigra pars reticulata to the
cortex and brainstem motor system, via thalamus, causing
the manifestation of bradykinesia (slowness of movement),
tremor and rigidity [60].
The role of the nigrostriatal dopaminergic neuronal loss
in the pathogenesis of PD has been questioned, since the
hyperactivity of STN usually occurs before the appearance of
parkinsonian signs, and is not correlated with inhibition of
GPe activity. Indeed, the increased activity of STN, which is
predominantly glutamatergic, might cause excitotoxicity and
consequently, neuronal death [60, 62]. Glutamate is an
excitatory neurotransmitter that can act on metabotropic and
ionotropic receptors, such as NMDA, AMPA and KA
receptors. Excitotoxicity can be the result of excessive
activation of ionotropic receptors, mainly NMDA receptor,
due to increased levels of glutamate in synaptic cleft.
Overactivation of NMDA receptors can trigger a massive
influx of extracellular Ca2+ , leading to neuronal
dyshomeostasis and, ultimately, cell death [63]. Nigral
dopaminergic neurons have ionotropic glutamate receptors.
Therefore, the STN disinhibition that follows nigrostriatal
damage might cause glutamatergic overstimulation of
residual neurons of the SNc, causing a vicious cycle in
which nigrostriatal damage causes STN hyperactivity, which
in turn worsens the nigrostriatal damage. Thus, in addition
to have a role in the development of PD motor symptoms,
the STN may also be involved in the progression of PD [62,
64]. Accordingly, studies performed in animal models of PD
have reported that reduction or inhibition of STN activity
prevents dopaminergic neuronal loss in the SNc [65, 66].
Since PD pathogenesis depends on the degeneration of
several neurotransmitter systems, therapeutic strategies to
control PD should not be the only focus on the restoration
of the nigrostriatal dopaminergic system [60].
Oxidative Stress
All aerobic organisms are continually exposed to
oxidative stress. Oxidative and reductive reactions involve
the transfer of electrons, which can lead to the generation of
free radicals. Free radicals, molecules with unpaired
electrons, are unstable reactive species that can extract
electrons from neighboring molecules to complete their own
orbital [67]. This leads to oxidation of cellular molecules,
namely DNA, proteins, and membrane lipids.
The fact that age is a key risk factor in PD provides
considerable support for the free radical hypothesis, because
Oliveira et al.
effects of the attacks by free radicals can accumulate over the
years [68]. Moreover, dopamine metabolism and/or
impairment of oxidative phosphorylation produce reactive
oxygen species that contribute to an overall increase in
oxidative damage.
There are several potential sources of oxidative damage in
PD. Substantial data from post-mortem studies support an
increased oxidative damage in PD. A consistent increase in
lipid peroxidation and an increase in protein carbonyl groups
have been reported in PD substantia nigra [69, 70]. A 138%
increase in 8-hydroxy-2-deoxyguanosine concentration in
DNA was observed in PD substantia nigra [71]. In addition,
reduced glutathione, a very important antioxidant in the
brain, is markedly decreased in the substantia nigra of PD
patients [72]. A decrease in catalase and glutathione
peroxidase activities in PD was reported, but superoxide
dismutase activity in substantia nigra of PD patients was
shown to be increased [73, 74]. Also relevant is the fact that
the iron levels, which in a non-pathological situation are
significantly higher in substantia nigra than in other brain
regions, further increase in substantia nigra of PD patients
[74].
Nigral dopaminergic neurons are particularly exposed to
oxidative stress, since dopamine can easily auto-oxidize into
toxic dopamine-quinone species, superoxide radicals and
hydrogen peroxide [75]. Moreover, dopamine can be
metabolized via enzymatic deamination by monoamine
oxidase (MAO), with the production of the non-toxic 3,4dihydroxyphenylacetic acid (DOPAC) and hydrogen
peroxide [76]. Superoxide radical can be converted to
hydrogen peroxide by superoxide dismutase or into the more
toxic peroxynitrite radical in the presence of nitric oxide.
Hydrogen peroxide can be rapidly converted to a more
reactive radical, hydroxyl radical, in a reaction catalyzed by
iron, which is highly abundant in substantia nigra pars
compact [77]. The loss of protein sulphydryl groups induced
by dopamine toxicity is associated with the loss of
monoaminergic striatal terminals [78]. Oxidized dopamine
has been shown to stabilize the formation of α-synuclein
protofibrils that are claimed to be the more toxic form of αsynuclein [79], inhibiting its conversion to insoluble fibrils
[80].
A dual relationship exists between α-synuclein and the
production of free radicals. Not only can the oxidative
process can transform non-aggregated α-synuclein into its
aggregated form, but also by itself may be able to generate
hydrogen peroxide in vitro [81]. Therefore, it could be
speculated that once an oxidation process starts, an
enhancement of α-synuclein aggregation occurs leading to an
increased neurotoxicity, with release of cellular iron, which
catalyzes further oxidations, initiating a positive feedback of
oxidative neurodegeneration. Moreover, high expression
levels of the wt and mutant forms of α-synuclein cause an
increase in reactive oxygen species (ROS) production [82].
Also important is the fact that α-synuclein toxicity in
cultured neurons is blocked by antioxidants [83].
Further evidence that oxidative stress participates in the
loss of nigral neurons in PD was obtained from studies
using the parkinsonism-inducing drugs MPP + and rotenone.
MPP + is taken up into dopaminergic neurons by DAT, and
in addition to inhibiting complex I of the mitochondrial
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respiratory chain, it has a high affinity for VMAT2 and, as a
result, it can be taken into dopaminergic vesicles. Thus, in
addition to depleting ATP from dopaminergic neurons,
MPP + is also able to redistribute dopamine into the cytosol
leading to dopamine-dependent oxidative stress. Rotenone
can also block complex I activity and may increase the levels
of cytoplasmic dopamine by altering its vesicular storage
[52].
treatment, both wt and mutated α-synuclein cells showed a
decrease in mitochondrial membrane potential, indicating a
correlation between mitochondria and α-synuclein. In
addition, it has been shown that α-synuclein expression in
mice substantia nigra was insufficient to produce
mitochondrial pathology, which could be observed with
MPTP supplementation [95].
Impairment in the Proteasomal System
Mitochondrial Dysfunction
Mitochondria are the intracellular organelles responsible
for the supply of ATP; they are semiautonomous, they
contain their own DNA and protein synthesizing machinery,
although most of the proteins that reside in the mitochondria
are nuclear gene products [84]. Defects in the electron
transport chain within the mitochondria are major factors
contributing to the production of free radicals. It has been
described that mitochondrial function is altered in the course
of aging and also in PD, particularly an alteration in the
mitochondrial respiratory chain complex I [85]. Many
studies have shown that mitochondrial dysfunction is
implicated in the pathogenesis of PD [8, 86, 87, 88]. Two
consistently identified biochemical abnormalities in PD
substantia nigra are mitochondrial complex I deficiency and
increase in free radical production [25, 89]. The complex I
defect in idiopathic PD is of particular interest, since
inhibitors of this complex cause nigral cell death in humans
and in animals.
Co-enzyme Q10 (CoQ10), which improves electron
respiratory chain function and scavenges free radicals, has
been described to exist at a lower concentration in patients
with PD [90], probably due to the complex I defect observed
in these patients [91].
Parkinsonism was induced in humans by MPP+ , a
metabolite of MPTP [92], and more recently, the pesticide
rotenone was shown to induce neurodegenerative changes
similar to PD in rats [36], both molecules being complex I
inhibitors. Further support of mitochondrial involvement in
the pathogenesis of PD was obtained using a cybrid
technique, that uses cell lines without a functional
mitochondria fused with mitochondria from platelets (or
other tissues) obtained from PD patients. Cassarino and
collaborators [93] observed a decrease in complex I activity
and an increased production of free radicals in PD cybrids,
suggesting that the decrease in complex I activity present
either in PD brains or platelets, can be responsible for the
damaging amounts of free radicals observed. Complex I
deficiency and free radical damage are inter-related, since a
defect in complex I causes an increase in the release of
superoxide ions from the respiratory chain and, in turn, free
radicals increase leads to an impaired activity of respiratory
chain proteins. Much of the cellular damage caused by
rotenone in rodents seems to be mediated not by ATP
depletion but by generation of free radicals [36].
Moreover, the relationship between mitochondrial
function and α-synuclein expression has been studied to
address the possible pathological mechanism of PD. Orth
and colleagues [94] showed that mutant or wt α-synuclein
did not alter mitochondrial respiratory chain activity or
mitochondrial membrane potential. However, upon rotenone
An involvement of the proteasomal system in PD has
been described, partially because mutations in UCHL1 and
parkin showed a contribution to neurodegeneration in PD.
Moreover, a decrease in the proteasome peptidase activity in
the substantia nigra of sporadic PD patients has been
described [96, 97]. McNaught and co-workers [97] also
showed a decrease in the expression of proteasomal αsubunits in substantia nigra of PD patients. More recently,
Grüblatt and collaborators [98] showed modifications of the
gene expression profile in ubiquitin-proteasome system in
substantia nigra pars compacta of sporadic PD patients.
These data are in accordance with McNaught and collegues
[99] reports showing a decreased expression of the 20S
proteasome α-subunits, decreased protein expression levels
of some 19S subunits and functional deficits in the 26/20S
proteasome activity in substantia nigra pars compacta of
sporadic PD patients. Other studies correlate α-synuclein
with proteasome function, since α-synuclein can interact
with a subunit of the proteasome regulatory complexes
[100], and proteasome subunits co-localize in LBs [101]. It
has been demonstrated that proteasome pathway may
mediate the degradation of α-synuclein. This degradation,
proposed by several authors [102, 103, 104], seems to be
mediated by the 20S proteasome, indicating that impairment
in the proteasome activity could promote α-synuclein
accumulation and further aggregation. These conclusions
were supported by several in vitro studies demonstrating that
proteasome inhibitors promote α-synuclein aggregation
[103, 105, 106]. On the other hand, it has been shown by
several groups that α-synuclein overexpression produces a
decrease of proteasome peptidase activity [107, 108]. A
decrease in proteasome activity in PC12 cells expressing
mutant α-synuclein was also described [109]. Taken
together, these results suggest that
α-synuclein
overexpression may lead to proteasome inhibition, creating a
positive feed-back loop, that will increase α-synuclein
accumulation and aggregation. In agreement with in vitro
studies is the observation that a duplication or triplication of
the α-synuclein gene leads to PD [10, 11]. Nevertheless,
this issue is still controversial since it has been described
that α-synuclein expression either in vivo (transgenic mice
for human α-synuclein A30P) and in vitro (PC12 cells
overexpressing wt A30P and A53T α-synuclein), did not
affect proteasome function, measured by proteasome
peptidase activities or proteasome subunits expression [110].
Moreover, the well-known complex I inhibitors, MPP+ and
rotenone, induce a proteasome activation in rat
mesencephalon primary culture [106]. It has been
demonstrated that proteasome inhibitors render cells more
vulnerable to death [109, 111, 112]. On the other hand,
Sawada and colleagues [106] showed that proteasome
inhibition blocked MPP+ or rotenone induced cell death.
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Chaperones
Molecular chaperones are involved in several important
cellular processes. They bind unfolded proteins and can
either mediate correct folding and compartmentalization or
proteasomal degradation. This includes normal proteins that
are intended for deactivation or abnormal proteins that are
mislocalized or are defective, due to misfolding or chemical
modification, and whose accumulation could be toxic [113].
It is generally accepted that PD is a protein
conformational disease, being the hallmark event a change in
its structure. Recently, it has been described that chaperones
may play a role in this conformational change. Furthermore,
immunostaining studies showed the presence of chaperons in
LBs of human postmortem tissue, also suggesting that
chaperones may play a role in Parkinson's disease
progression [114]. Most studies in PD focus on the role of
chaperones in α-synuclein fibril formation, and it has been
proposed that the expression of small heat shock proteins
(sHsp) reflect a defensive response to diminish α-synuclein
fibril formation and subsequent toxicity. It was
demonstrated that the molecular chaperone Hsp70 could
reduce the amount of misfolded, aggregated α-synuclein
species in vivo, therefore protecting cells from α-synucleindependent toxicity [115]. Additionally, it has been
demonstrated in vitro that over expression of the heat shock
protein HSP27 has a protective anti-apoptotic outcome
against the toxic role of wt and particularly of mutant αsynuclein. On the other hand, HSP70 can protect from the
toxic effect of the wt protein, but has no action against the
mutant proteins, while HSP56 has no protective effect in
this system [116].
NEUROINFLAMMATION
The hallmark of brain inflammation, also designated as
neuroinflammation, is the activation of glial cells, mainly
microglia. An intense glial (astrocytes and microglia)
activation was observed in substantia nigra of PD patients
[117] and in PD animal models [118]. A large number of
recent studies postulate that microglia and astrocytes play a
key role in progressive degeneration of DA neurons in PD.
Microglia, the immune effector cells of the brain, are
sensitive to minor disturbances in brain homeostasis, and
become activated during injurious or neuropathological
conditions. Although these cells can have a neuroprotective
function by the secretion of neurotrophic factors and
elimination of cellular debris and/or pathogens, activated
microglia can also trigger neuronal damage via release of
pro-inflammatory and neurotoxic factors. These factors
include the pro-inflammatory cytokines, interleukin 1β, (IL1β), IL-6, tumor necrosis factor-α (TNF-α), T-cell
activation-associated cytokine (IL-2), interferon-γ (IFNγ),
ROS and reactive nitrogen species, (RNS), proteases and
acute phase proteins. Astrocytes can be activated by
inflammatory or neurotoxic factors released by reactive
microglia and/or injured neurons. Reactive astrocytes secrete,
primarily, neurotrophic factors, but they can also produce
inflammatory and neurotoxic factors similar to those secreted
by activated microglia. Therefore, both glial cells, depending
on the degree of activation, can influence the fate of the
injured neurons. In PD brain, the dying DA neurons and the
Oliveira et al.
consequent biochemical environment changes can be the
trigger of microglia and astrocyte activation [119, 120].
Microglia can also be activated by products of the classical
component cascade, such as C-reactive protein, that is
upregulated in PD brain [121] Pro-inflammatory cytokines
once released from reactive glial cells, can bind to their
receptors on DA neurons to activate transduction pathways
that trigger apoptosis. In addition, the substances derived
from activated glial cells can trigger the expression of
inducible nitric oxide synthase (iNOS) or cyclooxygenase-2
(COX-2) within these cells, thus leading to reactive nitrogen
and oxygen species production. These reactive species can
cross the cell membrane and cause oxidative damage,
especially in DA neurons that are extremely vulnerable to
oxidative stress. An intense gliosis was observed around DA
neurons in PD brain, despite a long (3-16 years) neuronal
survival, and it was postulated that after a primary neuronal
insult of environmental or genetic origin, glial activation
might perpetuate the degeneration of DA neurons [122].
MECHANISMS OF CELL DEATH
Depending upon the stimuli, cells might die by necrosis,
apoptosis or autophagy. It is still not clear what type of cell
death occurs in PD brains, although the slow and
progressive degeneration of dopamine neurons is more
compatible with apoptosis. The cell death of dopaminergic
neurons in substantia nigra pars compacta causes a
remarkable loss of dopamine in caudate/putamen nuclei.
Necrotic cell death exhibits cytoplasmic and nuclear
swelling, membrane breakdown, leading to the leakage of
cytosolic contents and inflammation. Necrosis may occur in
PD when neurons are exposed to high glutamate
concentrations, involving an excitotoxic pathway [123].
Although there is no available data in literature describing
necrotic cells in substantia nigra of PD patients, the
hypothesis of their existence cannot be disregarded, since
their rapid elimination may constitute the reason why they
are not detected.
Autophagic cell death is characterized by the vacuolation
of the cytosol within a double-membrane structure, the
autophagosome, which fuses with the lysosome for
subsequent digestion [124]. As a consequence, the
destruction of the cytoplasm occurs, maintaining the
integrity of the nucleus (in contrast to apoptosis) and of the
plasma membrane (in contrast to necrosis). This kind of cell
death has been observed in nigral neurons of PD patients
[125]. Gómez-Santos and co-workers [126] showed that
dopamine induced autophagic cell death in a human
neuroblastoma cell line. An autophagic cell death in PC12
cells expressing the A53T α-synuclein mutant has also been
described [127]. It is relevant to elucidate that apoptotic
signals may also activate autophagy as an alternative
mechanism of cell death [128]. Recently, it was
demonstrated by Rideout and collaborators [129] that
proteasomal inhibition in primary neurons leads to
autophagy, possibly in response to the apoptotic pathway.
Apoptotic cell death depends on different interacting
signaling pathways, and diverse insults may activate
alternative pathways leading to nuclear chromatin
condensation and DNA fragmentation. Apoptotic cells show
Neurodegenerative Pathways Towards Therapeutical Strategies
Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 411
membrane blebbing, DNA fragmentation and do not induce
immune response. Apoptosis occurs during normal cell
development but can also be responsible for neuronal death
in some diseases, and there is increasing evidence that it is
also involved in PD. [130]. Apoptotic features have been
shown in PD patients, like fragmented nuclei and caspase
activation [131, 132, 133]. Moreover, it has been described
that pro-apoptotic genes (c-Jun, P53, GAPDH, Bax) are up
regulated in substantia nigra of PD patients [134], and five
fold higher caspase 3 positive neurons were found in patients
as compared to controls [132]. This subject is still
controversial, since in the end-stage of the disease, there is
little evidence of apoptosis [135, 136]. In addition, it was
demonstrated that 6-hydroxydopamine (6-OHDA), a
dopamine quinone derivative, present in post-mortem PD
brains [137], upregulates c-Jun and activates caspase 3 in
vitro [138].
In vitro studies have shown that chronic administration
of rotenone in a neuroblastoma cell line increases basal and
H2O2 induced caspase dependent cell death [34]. It has been
demonstrated that MPP + induced mitochondrial cytochrome
c release in a human neuroblastoma cell line [139], and
apoptotic cell death both in vitro [140] and in vivo [141,
142, 143].
Recently, Yamada and co-workers [144] observed that
overexpression of α-synuclein in rat substantia nigra induced
a 50% loss of dopaminergic neurons and caspase 9
activation. Moreover, the study performed by Watabe and
Nakaki [145] showed that rotenone induces neuronal death in
SH-SY5Y cells via Bad dephosphorylation and caspase 9
activation.
THERAPEUTIC STRATEGIES
Drugs Involved in Neurotransmission Improvement
L-dopa: Replacement of striatal dopamine with the
precursor of dopamine, L-dopa, is the most effective
pharmacological treatment of PD. Since dopamine itself
could not access the brain directly, its natural precursor Ldopa was used in clinical trials. By 1967, Cotzias and coworkers [146] were able to announce that large oral doses of
L-dopa resulted in a therapeutic success in the treatment of
the disease. However, it was discovered that although its
initial results were dramatically effective, a growing
tolerance developed, resulting in a need to increase dosages
over time. Eventually, side effects resulting from high doses
of the drug, such as dyskinesias, gastrointestinal symptoms,
insomnia, hallucinations and psychosis, outweigh any
improvement observed from the correction of dopamine
deficiency [147]. It was suggested that the damaging side
effects of L-dopa’s use stem not directly from the drug but
from its oxidation products, which include dopachrome and
other chrome indoles which are hallucinogenic, toxic to
neurons and have been shown to hasten death in PD patients
[75, 148].
Several new dopaminergic drugs are in advanced clinical
development and will be released soon to the market:
sumanirole, rotigotine, L-dopa methylester and ethylester,
and the triple combination of L-dopa/carbidopa/entacapone,
Piribedil [149].
Drugs Acting at the Dopamine Transporter Level: These
drugs increase the synaptic levels of dopamine by blocking
the action of the synaptic dopamine transporter. Brasofensine
is one of these drugs, producing a potentiation of the effects
of L-dopa in MPTP-treated monkeys without inducing
dyskinesia [150]. In 8 patients receiving the drug, an initial
improvement over a 4-week period was observed, but by the
end of the study, this improvement had been lost, and no
significant differences were shown against placebo [150].
Selective Dopamine Receptor Agonists: D1 receptors have
been repeatedly involved in the origin of L-dopa-induced
dyskinesias, and selective D1 receptors agonists have been
shown to be highly effective in MPTP-treated monkeys,
producing a natural motor response without dyskinesia [151,
152]. Dihydrexidine, a high-affinity full D1 agonist,
produced a dramatic reduction of parkinsonian signs in
severely afflicted MPTP-treated monkeys
[153].
Furthermore, Blanchet and co-workers [154] performed a
clinical trial where 4 patients received dihydrexidine
intravenously. Although three patients were withdrawn from
the study due to severe postural hypotension, the remaining
patient showed a 70% improvement in Unified Parkinson’s
Disease Rating Scale (UPDRS) score.
ABT-431, another D1 agonist, showed positive effects
against parkinsonism and dyskinesia in MPTP-treated
monkeys [155]. However, when tested in humans with PD
and motor complications, ABT-431 had a similar action to
L-dopa, but without significant modification of dyskinesia
[156, 157].
Partial Dopamine Receptor Agonists: This class of
compounds exerts agonist activity at denervated
supersensitive sites and competitively inhibits complete
agonists at fully innervated normosensitive receptors. Thus,
their therapeutic window appears to be higher than full
agonists mainly in patients with L-dopa-induced dyskinesia
or psychiatric disturbances. Terguride, a partial D2 receptor
agonist, exhibited both antiparkinsonian and antidyskinesia
effects in MPTP-treated monkeys [158], but when
administered to patients with motor complications, the
results were inconsistent. In some cases, the drug reduced
dyskinesia without worsening parkinsonism but, in others,
it worsened both dyskinesia and PD symptoms [159].
Non-dopaminergic drugs: Other pharmacological
strategies include adenosine A2a receptors antagonists, α2
noradrenergic receptor antagonists, GABAergic drugs, drugs
acting on serotoninergic
transmission,
glutamate
antagonists, cannabinoids agonists and antagonists and
opioid receptor agonists and antagonists [for review see:
149]. Table 1 shows the effects of some of these agents in
animal and human studies.
The efficacy of the drugs above mentioned is lower than
that of L-dopa, but their initial or combined use with L-dopa
might help to avoid or delay the occurrence of drug-induced
dyskinesias and neuropsychiatric adverse effects, which often
complicate the medical treatment of PD [191]. These
complications have prompted many additional strategies to
lessen drugs effects, for example, with continuous drug
infusions by transdermal, intravenous or intraduodenal drugdelivery systems [192].
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Table 1.
Oliveira et al.
Effect of Some Non-Dopaminergic Agents in Animal Models and PD Patients
Non-dopaminergic agents
Positive effects
Negative or no effects
Adenosine A2a receptor antagonists
[160, 161, 162, 163)
[164]
[165, 166, 167]
[167]
GABAergic drugs
[168, 169, 170, 171, 172]
[173, 174, 175, 176]
Drugs acting on serotoninergic transmission
[177]
[164, 178]
Glutamate antagonists
[179, 180, 181, 182]
[183, 184]
Cannabinoids agonists and antagonists
[185, 186]
Opiod receptor agonists and antagonists
[187, 188]
2 noradrenergic receptor antagonists
Antioxidant Therapies
Co-enzyme Q is an essential co-factor of the electron
transport chain (accepts electrons from complexes I and II)
and possesses antioxidant properties. Beal and colleagues
[193] reported that the administration of CoQ10 to 24month-old mice treated with MPTP induced a significant
protection against neuronal dopamine depletion and loss of
tyrosine hydroxylase. Muller and collaborators [194]
performed a monocenter, parallel, placebo controlled,
double-blind trial aimed to determine the symptomatic
response of daily oral application of 360 mg CoQ10 on
scored PD symptoms in 28 treated and stable PD patients.
They observed a significant mild symptomatic benefit and a
better improvement of performance compared with placebo.
Recently, the safety and tolerability of high dosages of
CoQ10 were studied in 17 patients with PD in an open label
study [195]. The subjects received an escalating dosage of
CoQ10 (1200, 1800, 2400, 3000 mg/day) with a stable
dosage of vitamin E (1200 IU/day). 13 patients achieved the
maximal dosage without adverse effects related with CoQ10.
Furthermore, the plasma level reached a plateau at the 2400
mg/day dosage and did not increase further at the 3000
mg/day, dosage suggesting that in future studies of CoQ10
in PD, a dosage of 2400 mg/day (with 1200 IU/day vitamin
E) is an appropriate highest dosage to be studied.
Recently, Zhang and co-workers [196] reported the
results of a prospective study, which showed that high
dietary intake of food rich in vitamin E is associated with a
reduced risk of developing PD. However, no protective effect
was observed with supplemental vitamin E or C, or with
dietary vitamin C or carotenoids. The Parkinson Study
Group [183] tested vitamin E at a daily dose of 2000 IU in a
prospective, placebo-controlled, double blind trial of 800
previously
untreated
patients.
The
investigators
simultaneously tested the effect of deprenyl (MAOB
inhibitor) and vitamin E by the use of a 2x2 factorial design.
The results obtained showed that vitamin E failed to delay
the rate of disease progression compared with placebo,
whether administered alone or in combination with deprenyl.
These results are supported by a recent study showing that
vitamin E is ineffective, because it did not enhance the
activity of nigrostriatal dopaminergic neurons [197].
Ginkgo biloba has been reported to protect dopamine
neurons from MPTP-induced neurotoxicity [198]. Recently,
Kim and collaborators [199] demonstrated that EGb 761
[189, 190]
(extract of Ginkgo biloba) reduces the behavioral deficit
caused by 6-hydroxydopamine-induced neurotoxicity in the
nigrostriatal dopaminergic system of the rat brain.
Furthermore, it has been demonstrated in a rat model of PD
that the combined use of EGb with L-dopa may be a
workable method to treat PD and may be better than using
L-dopa alone [200].
Estrogens
Accumulating scientific evidence of estrogen beneficial
effects on dopaminergic neurotransmission, as well as
increased interest in estrogens role in cognition and
dementia, led to renewed efforts to study its effects in PD.
Two recent investigations have demonstrated that estrogen
administration is beneficial for the symptoms of PD [201,
202]. The double-blind trial performed by Tsang and coworkers [202] showed a significant improvement in motor
function in postmenopausal women taking estrogen as
compared with placebo treatment. In the second study,
Saunders-Pullman and colleagues [201] conducted a
retrospective chart review of 138 women who had PD for
less than 5 years and who had not taken L-dopa. They found
a positive association between estrogen use and reduced
severity of symptoms. However, results from other studies
have been less clear about the benefits of estrogen in
ameliorating PD symptoms. In two cases reported in Lancet
[203], oral conjugated estrogens abolished dyskinesia while
aggravating PD symptoms, suggesting an antidopaminergic
effect. However, the study performed by Blanchet and
collaborators [204] showed that 17β-estradiol appears to
display a slight pro-dopaminergic effect without consistently
altering dyskinesias.
Cultured mesencephalic neurons incubated in medium
containing estradiol were resistant to bleomycin sulfateinduced apoptosis [205]. The effect induced by estradiol was
blocked by the specific estrogen receptor antagonist ICI
182,780, which suggests that the neuroprotective effect was
mediated by classical estrogen receptors [205]. Preincubation
with estradiol similarly provided significant neuroprotection
against glutamate-induced neurotoxicity [206]. It has been
shown that the direct infusion of 6-hydroxydopamine
(OHDA) into the striatum of ovariectomized rats
significantly reduced the dopamine concentrations within the
lesioned side [207]. However, animals that had been
implanted with a time-release estrogen pellet, underwent
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Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 413
significantly less dopamine depletion after injection of
OHDA [207]. Recently, Shughrue [208] showed that mice
pretreated with estradiol present less MPTP-induced tyrosine
hydroxylase loss when compared with untreated mice.
Quesada and Micevych [209] reported that pretreatment of
ovariectomized female mice with estrogen or insulin growth
factor 1 (IGF-1) significantly prevented 6-OHDA-induced
loss of substantia nigra compacta neurons (20% loss) and
tyrosine hydroxylase immunoreactivity in dopamine fibers
in the striatum (<20% loss) and prevented the loss of
asymmetric forelimb use. Blockage of IGF-1 receptors by
intracerebroventricular JB-1, an IGF-1 receptor antagonist,
attenuated both estrogen and IGF-1 neuroprotection of
nigrostriatal dopaminergic neurons and motor behavior.
These findings suggest that IGF-1 and estrogen acting
through the IGF-1 system may be critical for neuroprotective
effects of estrogen on nigrostriatal dopaminergic neurons in
this model of Parkinson’s disease.
Non-steroidal Anti-Inflammatory Drugs (NSAID)
The possible anti-inflammatory strategy against
neurodegeneration in PD is supported by experimental
studies using some NSAID on in vitro and in vivo models
of PD. It has been shown that the pretreatment with sodium
salicylate, aspirin and meloxicam, a preferential COX-2
inhibitor, significantly and almost completely protected
MPTP-induced striatal dopamine depletion, locomotor
activity and loss of nigral dopaminergic neurons [210-213],
although other non-selective NSAID (paracetamol,
diclofenac, ibuprofen, indomethacin) and dexamethasone
showed no protective effects [210]. Breidert and colleagues
[214] showed that oral administration of pioglitazone, a
PPARγ agonist, attenuated the MPTP-induced decrease in
striatal dopamine levels and dopaminergic cell loss in the
substantia nigra [214]. Recently, Chen and collaborators
[215] observed that individuals who reported regular use of
non-aspirin NSAID at the beginning of the study had a
lower risk of PD than non-regular users during the followup. Compared with non-users, a non-significant lower risk
of PD was also observed among individuals taking 2 or
more tablets of aspirin per day. These results suggest that
the use of NSAID may delay or prevent the onset of PD.
Surgical Treatment
The efficiency of L-dopa declines over time in a majority
of patients for whom motor fluctuations and L-dopa-induced
dyskinesias become frequent [191]. This fact, together with
refined stereotaxic procedures, sophisticated brain-imaging
techniques and advanced computer programs, has led to a
resurgence of surgical methods for the treatment of PD.
Ablative techniques, deep brain stimulation, and neural
transplantation are now used to correct the striatal loss of
dopamine and related functional disturbances in the basal
ganglia circuitry [192, 216, 217].
Neural Transplantation: The efficacy of cell replacement
for the treatment of PD is based on two hypothesis: 1) the
predominant symptoms develop because of the dysfunction
or loss of the dopaminergic neurons in the nigrostriatal
pathway; 2) dopaminergic neurons grafted into the
dopamine-deficient striatum can replace the neurons lost as a
result of the disease process and can reverse, at least in part,
the major symptoms of the disease [218, 219]. Lindvall et
al. [219] reported that mesencephalic dopamine neurons,
obtained from human fetuses of 8 to 9 weeks gestational
age, could survive in the human brain and produced marked
and sustained symptomatic relief in a patient severely
affected with idiopathic PD. Furthermore, experiments in 6OHDA-lesioned rats with L-dopa-induced dyskinesia have
shown that grafting dopaminergic fetal cells into the
striatum produced an improvement in motor behavior,
including dyskinesia, which was accompanied by a reversal
of the molecular mechanisms theoretically responsible for
dyskinesia [220]. Paradoxically, two recently published
double-blind studies using this technique have not been able
to demonstrate significant efficacy and were both
complicated by the occurrence of off-medication dyskinesias
[217, 221, 222]. The use of this therapeutic strategy is
furthermore hampered by ethical and practical considerations,
owing to the need for large amounts of immature
dopaminergic nervous tissue (three to four fetuses for each
side of the brain, obtained at a very narrow gestational age)
due to an estimated 10% survival rate of the transplanted
tissue and the lack of consensus regarding the implantation
technique.
The rationale for the use of drugs that will improve the
viability of donor cells and/or transplanted cells is that such
pharmacological treatment will result in a better functional
outcome. Neurotrophic factors are potential therapeutical
agents that could enhance viability and functional effect of
neural transplantation therapy. Hoffer and colleagues [223]
initially demonstrated that a single intraventricular injection
of glial-cell-derived neurotrophic factor GDNF to a normal
rat induces a long-term increase in striatal dopamine. Most
critically, GDNF has been able to prevent the structural
and/or functional consequences that are engendered in
virtually every rodent model of PD including those with
lesions induced by OHDA, methamphetamine, or axotomy
as well as the degenerative changes associated with aging
(for review see: 224). Based on these studies, experiments
were performed in normal and parkinsonian monkeys, and
similar benefits of GDNF treatment were realized [225]. This
preclinical demonstration of the efficacy of GDNF in animal
models of PD has prompted small clinical trials of such
therapy in patients. In a PD patient who received monthly
intraventricular injections of GDNF, parkinsonian symptoms
continued to worsen [224]. These observations support the
contention that GDNF might only be efficacious when
initiated in early stage PD. Moreover, in this GDNF-treated
patient, there was no evidence of restoration of nigrostriatal
neurons and no indication of intraparenchymal diffusion of
the GDNF to relevant brain regions. These findings suggest
that the route of delivery (intraventricular) of GDNF is not
an effective approach. Recently, Gill and co-workers [226]
reported on the direct lentiviral delivery of GDNF into the
putamen, the brain area with the most severe dopamine
depletion, in five patients with PD. The effects on
parkinsonism, openly assessed, were highly beneficial. After
1 year, there was a 39% improvement in the off-treatment
motor score and a 61% improvement in the activity of daily
living score of the unified PD rating scale. Drug-induced
dyskinesias were reduced by 64%. Fluorine-18-labeled
dopamine uptake was increased in the putamen, which
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Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4
suggests a direct effect of GDNF on dopamine function.
Similarly, it has been shown that transplantation of human
pigmentary epithelial retinal cells [227] have led to
remarkable improvements in a few PD patients. However,
these studies need to be confirmed in controlled trials.
Ablative Technique: Disruption of the proposed
hyperactive STN or the increased inhibitory output from GPi
by localized stereotaxic lesions, aided by advanced brain
imaging, microelectrode recordings and pre-lesional
stimulation of the target (macrostimulation), has been shown
to be an effective and reasonably safe procedure [216]. These
interventions
alleviate contralateral L-dopa-induced
dyskinesias and improve parkinsonian rigidity, tremor and
to a lesser extent akinesia, however, misplaced lesions might
cause irreversible neurologic, cognitive and neuropsychiatric
adverse effects [216].
Deep brain stimulation: The hyperactive pathways from
GPi and STN might also be modulated by implanted
electrodes, which block the neural activity in their vicinity
with a high-frequency electrical current [192, 216]. This
procedure is called deep brain stimulation (DBS) and has
proven very efficient in the treatment of PD complicated by
motor fluctuations and L-dopa-induced dyskinesia [228].
Recently, the effects of DBS of the STN were studied in 52
consecutive patients (13 over age 70, 15 under age 60, 24
age 60 to 70). All groups showed improvement of motor
fluctuations and dyskinesia. Patients over age 70 had
worsening of the UPDRS motor scores on medication,
despite less medication reduction. Their activities of daily
living and axial succors worsened, particularly in those with
preoperative gait difficulties. Rodriguez-Oroz and
collaborators [229] evaluated the long term (4 years) efficacy
of DBS of the STN in advanced PD. DBS provided a
significant and persistent anti-parkinsonian effect in
advanced PD 4 years after surgery. Another study indicates
that bilateral STN activates the projection of axons from the
STN, improving both ascending and descending pathways
from the basal ganglia and increasing the metabolism of
higher-order motor control in the frontal cortex.
DBS hereby represents a more flexible method for the
modulation of basal ganglia circuitry than ablative surgery,
and can be used bilaterally without the same occurrence of
neuropsychiatric and cognitive adverse effects [192, 216],
although a few cases of severe mood changes and slight
deficits in language abilities have been noted postoperatively
[230]. These adverse effects are probably related to the
influence of the electrode current on the limbic, associative,
and cognitive corticobasal ganglia-thalamo-cortical loops.
The most common adverse effects are however, related either
to the surgical implantation, which might cause hemorrhage
infections or seizures, or to the influence of the electrical
current on neighboring corticobulbar projections, which
might result in dyskinesia, diplopia, and paresthesias [228].
New Promising Strategies
It has been reported that F3 human multipotent neural
stem cells (NSC) genetically engineered to produce L-DOPA
by double transfection with cDNA for tyrosine hydroxylase
and guanosine triphosphate
cylohydrolase-1,
and
transplantation of these cells in the brain of Parkinson
Oliveira et al.
disease model rats led to L-DOPA production and functional
recovery [231]. Proactively transplanted F3 human NSC in
rat striatum, supported the survival of host striatal neurons
against neuronal injury caused by 3-nitropro-pionic acid in
an rat model of Huntington’s disease. Furthermore,
intravenously introduced through the tail vein, F3 human
NSC were found to migrate into ischemic lesion sites,
differentiate into neurons and glial cells, and improve
functional deficits in rat stroke models [231]. These results
indicate that human NSC should be an ideal vehicle for cell
replacement and gene transfer therapy for patients with
neurological diseases. In addition to immortalized human
NSC, immortalized human bone marrow mesenchymal stem
cell lines have been generated from human embryonic bone
marrow issues with retroviral vectors encoding v-myc or
telomerase gene. These immortalized cell lines of human
bone marrow mesenchymal stem cells differentiated into
neurons/glial cells, bone, cartilage and adipose tissue, when
they were grown in selective inducing media [231]. There is
further need for investigation into the neurogenic potential of
the human bone marrow stem cell lines and their utility in
animal models of neurological diseases. Zhao's Group [232]
provide evidence for the generation of dopaminergic
projection neurons of the type that are lost in Parkinson's
disease from stem cells in the adult rodent brain and show
that the rate of neurogenesis is increased after a lesion. The
number of new neurons generated under physiological
conditions in substantia nigra pars compacta was found to be
several orders of magnitude smaller than in the granular cell
layer of the dentate gyrus of the hippocampus. These data
indicate that neurogenesis in the adult brain is more
widespread than previously thought and may have
implications for our understanding of the pathogenesis and
treatment of PD. Recently, Hoglinger and collaborators
[233] provided ultrastructural evidence showing that highly
proliferative precursors in the adult subependymal zone
express dopamine receptors and receive dopaminergic
afferents. The authors observed that experimental depletion
of dopamine in rodents decreases precursor cell proliferation
in both the subependymal zone and the subgranular zone
being the proliferation restored completely by a selective
agonist of D2-like (D2L) receptors. In the same study, the
authors observed that the activation of D2L receptors in
neurosphere cultures, obtained from neural precursors from
the adult subependymal zone, directly increases the
proliferation of these precursors. Consistently, Hoglinger
and co-workers [233] observed that the numbers of
proliferating cells in the subependymal zone and neural
precursor cells in the subgranular zone and olfactory bulb are
reduced in postmortem brains of individuals with PD. These
observations suggest that the generation of neural precursor
cells is impaired in PD as a consequence of dopaminergic
denervation. In the same line, Van Kampen and collaborators
[234] demonstrated a two-fold induction of cell proliferation
(BrdU incorporation) in the subventricular zone and rostral
migratory stream of the adult Sprague-Dawley rat brain
following intrasubventricular administration of the dopamine
D(3) receptor agonist, 7-hydroxy-N,N-di-n-propyl-2aminotetralin (7-OH-DPAT) for 2 weeks. The number of
BrdU-positive cells was elevated ten-fold from very low
baseline levels in the neighboring neostriatum, another
region known to express D(3) receptors. These striatal BrdUpositive cells appeared within 3 days following intracerebral
Neurodegenerative Pathways Towards Therapeutical Strategies
Current Drug Targets - CNS & Neurological Disorders, 2005, Vol. 4, No. 4 415
infusion of 7-OH-DPAT
and
were
distributed
homogeneously throughout the striatum following systemic
administration. This suggests that these cells were originated
from resident progenitor cells rather than the subventricular
zone. Furthermore, dopamine D(3) receptor activation may
serve as a proneuronal differentiation signal, since 60-70% of
the new cells had neuronal markers following 7-OH-DPAT
infusion. These results suggest that the dopamine D(3)
receptor may be a good drug target for cell replacement
strategies, particularly because of the fact that its expression
is almost exclusively limited to the nervous system.
Furthermore, it has been shown that the subthalamic
injection of viral vectors expressing glutamic acid
decarboxylase (converts glutamate to GABA) can induce the
hyperactive excitatory glutamatergic cells in the STN to
express GABAergic inhibitory responses. It has been shown
that this alteration reversed a parkinsonian behavioral
phenotype in rats [235].
These approaches remain experimental therapies that
would require rigorous research efforts and clinical trials to
validate their potential for treatment of PD (Fig. 2).
Fig. (2). Schematic drawing illustrating the current pharmacological and surgical therapeutical strategies employed in PD.
Pharmacological treatment encloses several drugs acting at different levels: 1) dopaminergic drugs (such as precursors of dopamine,
dopamine selective/partial receptor agonists and inhibitors of MAOB and COMT); 2) antioxidants and estrogens primarily involved
in fighting oxidative stress and NSAID aimed to avoid inflammatory processes. Surgical treatment has emerged as an efficacious
experimental treatment for PD. The logistical and ethical issues that impede large-scale clinical trials with human fetal cells as donor
cell grafts led the scientists to explore other strategies such as genetically engineered cells, stem cells and/or immortalized cell lines
that express specific dopaminergic or neurotrophic factors, direct delivery (viral) of neurotrophic factors, ablative surgery and DBS.
For more detail see text.
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ABBREVIATIONS
[5]
6-OHDA = 6-hydroxydopamine
[6]
[7]
Ach
= Acetylcholine
CoQ10
= Coenzyme Q 10
COX-2
= Cyclooxygenase-2
DA
= Dopamine
DAT
= Dopamine transporter
DBS
= Deep brain stimulation
DOPAC = 3,4-dihydroxyphenylacetic acid
[8]
[9]
[10]
Gpe
= Globus pallidus pars externa
Gpi
= Globus pallidus pars interna
HSP
= Heat shock proteins
IFNγ
= Interferon-γ
IL-1β
= Interleukin 1β
[12]
IL-2
= Interleukin 2
iNOS
= Inducible nitric oxide synthase
[13]
[14]
LBs
= Lewy bodies
L-dopa
= Levodihydroxyphenylalanine
MAO
= Monoamine oxidase
MPP +
= 1-methyl-4-phenylpyridinium
MPTP
= 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NAC
= Non-amyloidogenic component
NSAID
= Non-steroidal anti-inflammatory drugs
PD
= Parkinson’s disease
PINK1
= PTEN-induced kinase 1
PLD2
= Phospholipase D2
RNS
= Reactive nitrogen species
ROS
= Reactive oxygen species
SHSP
= Smal heat shock protein
SNc
= Substantia nigra pars compact
STN
= Subthalamic nucleus
[23]
TH
= Tyrosine hydroxylase
[24]
TNF-α
= Tumor necrosis factor-α
[25]
[26]
[27]
[28]
UCHL1 = Ubiquitin-proteasome system
UPDRS = Unified Parkinson’s Disease Rating Scale
UPS
= Ubiquitin-proteasome system
[11]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[29]
VMAT2 = Vesicular monoamine transporter 2
[30]
wt
[31]
= wild-type
[32]
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