Download INTRODUCTION Neurotrophic factors (NTs) are secreted pro

NEUROTROPHIC FACTORS IN THE THERAPY OF PARKINSON’S DISEASE
Fabrizio Facchinetti, Salvatore Te rr a z z i n o ,
Antonello D’Arrigo, Luciano Rinaldi, Alberta
Leon
Research & Innovation, Padua
Reprint requests to: Dr Fabrizio Facchinetti, Research & Innovation, Via Svizzera 16, 35127 Padua, Italy.
e-mail: [email protected]
Many environmental and occupational chemicals are
known to affect the central and/or peripheral nervous
system, causing changes that may result in neurological and psychiatric disorders. Because of the limited
accessibility of the mammalian nervous tissue, new
strategies are being developed to identify biochemical
parameters of neuronal cell function, which can be
measured in easily obtained tissues, such as blood
cells, as potential markers of the chemically-induced
alterations occurring in the nervous system. This review includes a comparative analysis of the effects of
mercurials on calcium signalling in the neuroadrenergic PC12 cells and rat splenic T lymphocytes in an attempt to characterize this second messenger system as
a potential indicator of subclinical toxicity. The suitability of neurotransmitter receptors in blood cells,
such as the sigma binding sites, as biological markers
of psychiatric disorders is also discussed.
KEY WORDS: Brain-derived neurotrophic factor
(BDNF), dopaminergic neurons, gene therapy, glial
cell line-derived neurotrophic factor (GDNF), neurotrophic factors (NTs), Parkinson’s disease.
FUNCT NEUROL 2001;16: 45-56
INTRODUCTION
Neurotrophic factors (NTs) are secreted proteins that regulate survival and differentiation of
nerve cells. Nerve growth factor (NGF), the first
discovered NT, together with brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3)
and neurotrophin-4/5 (NT-4/5), form the classical family of NTs. However, many other growth
factors, which are effective also outside the nervous system, such as glial cell line-derived neurotrophic factor (GDNF), insulin-like growth
factor (IGF I), ciliary neurotrophic factor
(CNTF), basic fibroblast growth factor (bFGF)
and members of the tumor growth factor-beta
(TGF-beta) superfamily, fulfill the functional definition of “neurotrophic factors”. NTs were originally identified as target-derived compounds
regulating neuronal survival, growth and differentiation during development. In the adult brain,
NTs are necessary to maintain neuronal function
and phenotype. Increased expression of NTs is a
common response to brain damage (1) that may
have a neuroprotective role given the ability of
NTs to protect neurons against free radical damage, excitotoxicity and apoptosis (2).
Idiopathic Parkinson’s disease (PD) is a
neurodegenerative disorder pathologically de-
FUNCTIONAL NEUROLOGY (16)1 2001
45
F. Facchinetti et al.
fined by a selective loss of dopaminergic (DA)
neurons in the pars compacta of the substantia
nigra (SNc). Despite the great research efforts of
the last decade, the etiopathogenesis of PD is still
unknown. L-dopa and DA agonists are currently
used to alleviate symptoms of PD, but most
treated patients still develop a progressive functional disability that severely affects their quality
of life. Given the progressive nature of nigrostriatal degeneration in PD, therapeutic agents capable of slowing down or blocking this process
could be clinically significant.
It has been postulated that loss of DA neurons in PD may be accompanied by insufficient
trophic support leading to neuronal apoptosis.
However, it is not clear whether neuronal death
is predominantly apoptotic in PD, or whether a
reduced neurotrophic support is involved in the
neuronal loss accompanying the disease in humans. Regardless of the causes of PD, NTs, by
promoting DA neuronal growth and function
and by interfering with neurotoxic processes,
could be of therapeutic value.
THE GDNF FAMILY
Glial cell line-derived neurotrophic factor
was the first identified member of a family of
factors, which includes neurturin (NTN), enovin
and artemin (ART), all of which are distant
members of the transforming growth factor-beta
(TGF-beta) superfamily. GDNF was purified and
cloned from a rat glial cell line as a released
trophic factor specific for cultured primary DA
neurons (3). In addition, GDNF family proteins
are potent survival factors for several populations of central and peripheral neurons. At present, GDNF appears to be the most promising
trophic factor in the therapy of PD.
Glial cell line-derived neurotrophic factor
family members (GFMs) bind to a receptor complex formed by a binding component, the glycosyl-phosphatidyl inositol (GPI)-anchored GDNF
family receptor (GFR), and a signalling compo-
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FUNCTIONAL NEUROLOGY (16)1 2001
nent, the receptor tyrosine kinase Ret (for a review, see 4). According to one model of GDNF
signalling, GFR would appear to be involved in
GDNF binding with no intrinsic signalling ability, whereas Ret would appear to be responsible
for the intracellular signalling, but unable to bind
the factor in the absence of GFR.
The importance of GFMs and their receptors in the nigrostriatal circuit is well reflected by
their expression in that area. GDNF and NTN are
both present in developing striatal neurons and
GDNF mRNA has been detected in both cholinergic and GABAergic interneurons of the striatum (5). In the SNc, GDNF mRNA is detectable
in the majority of DA neurons. The mRNA for
the Ret receptor has also been found in nigral
DA neurons, whereas there is no clear indication
of its presence in the striatum. GFR receptors
show a distinct, albeit overlapping distribution,
being expressed both by nigral DA neurons and,
to some extent, also in the ventral striatum (6).
Effects of GDNF on DA neurons in culture
Glial cell line-derived neurotrophic factor
has the ability, in combination with other factors,
to convert rat fetal (E14.5) mesencephalic progenitor cells into tyrosine hydroxylase (TH)-immunoreactive neurons in vitro (7). In embryonic
midbrain cultures, GDNF promotes the survival
and inhibits the apoptosis of DA neurons (8). It
also promotes the biochemical and morphological differentiation of cultured ventral mesencephalic neurons by producing a significant increase in the number of neurite-bearing cells as
well as in the extent of their fiber network (9).
These effects are specific as GDNF does not increase total neuron or astrocyte numbers nor
does it increase transmitter uptake by GABAcontaining and serotonergic neurons (3). In addition, GDNF protects cultured DA neurons from
the neurotoxic effects of 1-methyl-4-phenyl-1,
2,3,6-tetrahydropyridine (MPTP) (9), and 6-hydroxydopamine (6-OHDA) (10). As exemplified
in Table I, GDNF robustly promotes the survival
Neurotrophic factors in the therapy of Parkinson’s disease
Table I - Overview of the effects of various neurotrophic factors on ventral mesencephalic neurons in culture
NTs
GDNF
NTN
BDNF
NT-3
NT-4/5
NGF
bFGF*
Survival
Neuritogenesis
Dopaminergic
phenotype
Neuroprotection
+++
+++
+++
++
+++
–
+++
+++
NR
++
++
+++
–
+
+++
NR
++
++
–
–
++
+++
NR
+++
NR
NR
NR
++
References
3, 8-10
26
50
29
29
51
39
The degree of efficacy in promoting survival, neuritogenesis, dopaminergic phenotype and neuroprotection is expressed in arbitrary units
where +++ = highest efficacy, and – = no efficacy.
Abbreviations and symbols: * = effect largely mediated via stimulation of astroglia; NTs = neurotrophic factors; GDNF = glial cell linederived neurotrophic factor; NTN = neurturin; BDNF = brain-derived neurotrophic factor; NT-3 = neurotrophin-3; NT-4/5 = neurotrophin-4/5; NGF = nerve growth factor; bFGF = basic fibroblast growth factor; NR = not reported.
and differentiation of midbrain DA neurons in
culture providing thereby the rationale for its application in animal models of PD.
The effects of GDNF in animal models of PD
Protection of midbrain DA neurons by
GDNF administration has been reported both in
rodent and in non-human primate animal models
of PD. In rats, the neuroprotective and/or behavioral effects of GDNF have been observed following: i) intranigral injections of 6-OHDA (11),
ii) intrastriatal injection of 6-OHDA (12), iii)
neurotoxic doses of methamphetamine and
MPTP (13) and iv) axotomy-induced degeneration of the medial forebrain bundle (14). Appropriate administration appears the crucial issue in
order to achieve maximal survival and trophic
effects on nigrostriatal DA pathway and longterm behavioral motor recovery.
Rats that receive unilateral 6-OHDA lesions can be induced to turn repetitively in circles in a direction either ipsilateral or contralateral to the lesion using amphetamine or apomorphine, respectively. Glial cell line-derived neu-
rotrophic factor, when intracerebroventricularly
injected, can access basal ganglia structures and
have beneficial, although transient, effects on
drug-induced rotational behavior (15). In the
MPTP-lesioned rhesus monkey, GDNF intracerebrally injected, either alone or in combination
with L-dopa and carbidopa, improves bradykinesia, rigidity and postural instability (16).
Intrastriatal GDNF treatment in parkinsonian rats preserves the nigrostriatal DA system
and increases axonal sprouting and reinnervation
of deafferented striatum to a degree sufficient to
reverse spontaneous motor deficits (17). On the
other hand, intranigral GDNF administration increases nigral DA neuron survival but does not
prevent striatal terminal degeneration in 6-OHDA-lesioned rats (12,15). Repeated nigral GDNF
injections lead neither to significant reinnervation of the lesioned striatal target nor to a behavioral recovery (12). Taken together, these results
indicate that the striatum is a more suitable site
for GDNF administration than the SNc in order
to prevent DA terminals from degeneration
and/or to facilitate behavioral recovery from motor asymmetry.
FUNCTIONAL NEUROLOGY (16)1 2001
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F. Facchinetti et al.
Table II - Overview of the effects of neurotrophic factors on the nigrostriatal DA pathway in animal models of PD
NTs
GDNF
NTN
NBN/ART
BDNF
NT-3
NT-4/5
aFGF
bFGF
Survival
Neuritogenesis
Dopaminergic
phenotype
Behavioral
recovery
References
+++
+/+++
++
++
++
++
+
+
+++
–
NR
++
–
++
–
+
+++
+/ –
++
–
–
NR
+
NR
+++
+/–
NR
++
–
++
+
+
17
26, 51–53
27
23, 36
24, 38
38
54, 55
56
The degree of efficacy in promoting survival, neuritogenesis, dopaminergic phenotype and behavioral recovery is expressed in arbitrary
units, where +++ = highest efficacy and – = no efficacy.
Abbreviations: NTs = neurotrophic factors; GDNF = glial cell line-derived neurotrophic factor; NTN = neurturin; NBN/ART= neublastin/artemin; BDNF = brain–derived neurotrophic factor; NT-3 = neurotrophin-3; NT-4/5 = neurotrophin-4/5; aFGF = acidic fibroblast
growth factor; bFGF= basic fibroblast growth factor; NR: not reported.
As exemplified in Table II, GDNF can have
potent effects on DA survival, phenotype and motor behavioral recovery in animal models of PD.
Despite these results, the main concern as regards
the applicability of GDNF in PD is the need to inject repeatedly large amounts of the peptide directly into the brain in order to obtain clinically significant effects.
GDNF in gene therapy
The possibility of expressing NTs locally in
specific brain areas may avoid potential side effects related to the activation of other brain structures. The introduction of specific therapeutic
genes into target brain areas is possible by means
of viral vector-mediated direct transfer. This genetic approach obviates the need for high doses
and repeated administrations. Therefore, gene
transfer based on viral vectors expressing NTs is
currently under extensive investigation in animal
models of PD.
Striatal injection of adenovirus (Ad) vectorexpressing GDNF significantly prevents degeneration of the nigrostriatal DA pathway and reduces
amphetamine-induced turning behavior in 6-OHDA- or MPTP-lesioned rats (18). The differential
effects of injecting Ad-GDNF near either nigrostriatal DA cell bodies or DA terminals has been
48
FUNCTIONAL NEUROLOGY (16)1 2001
compared in aged rats. While similar protection of
nigral DA neurons is observed, only striatal
GDNF injection protects striatal DA nerve terminals against 6-OHDA-induced damage and prevents behavioral deficits characteristic of unilateral DA depletion (19). Taken together, these reports
provide support for a potential therapeutic value
of GDNF expression driven by adenoviral vectors
in the attempt to prevent further cell death and/or
enhance the DA tone of surviving neurons in PD.
However, lack of sustained transgene expression,
high immunogenicity and potential toxicity may
limit the use of adenoviral vectors, at least those of
the first generation, for clinical purposes.
Recent developments in lentiviral and recombinant adeno-associated viral vectors (rAAV) have
resulted in transgene expression within the CNS
detectable for more than 6 months after injection
without cytotoxicity (20). A single administration
of rAAV-expressing GDNF enhances nigral DA
survival both before and after a striatal 6-OHDA
lesion (21). Protection of nigral DA neurons in
medial forebrain bundle (MFB)-axotomized rats is
also obtained after nigral injection of self-inactivating modified lentiviral vector-expressing
GDNF (22). Hence, GDNF gene therapy based on
novel viral vectors could, potentially, fulfill most
of the requirements to qualify as therapeutically
relevant for PD: i) biological efficacy; ii) long-
Neurotrophic factors in the therapy of Parkinson’s disease
term expression; iii) lack of toxicity coupled with
a wide therapeutic window. However, further studies are still necessary to evaluate long-term safety.
GDNF in cell replacement therapy
The ability of GDNF to regulate developmental neuron survival and differentiation of DA
neurons may be used to enhance the success of
cerebral grafts and to induce stem cells to phenotypically differentiate into DA neurons. GDNF
administration adjacent to the embryonic DA
graft not only increases graft survival but also restores the nigrostriatal DA pathway in unilateral
6-OHDA-lesioned rats, thus leading to a lasting
decrease in drug-induced rotational behavior
(23). Pre-treatment with GDNF is also effective
in increasing graft-derived fiber outgrowth and
improving contralateral forelimb function and
amphetamine-induced rotational behavior in unilateral 6-OHDA-lesioned rats (24). Co-graft of a
GDNF-secreting Schwann cell line with embryonic ventral mesencephalic cells improves graft
survival and promotes neurite outgrowth into the
host neuropil as well as axonal growth in the
striatum (25). Taken together, these reports suggest that GDNF could be effectively used in conjunction with cell replacement therapies.
GDNF-related NTs
Neurturin is expressed in the nigrostriatal system, and it exerts potent effects on survival and
function of midbrain DA neurons. NTN mRNA is
sequentially expressed in the ventral midbrain and
striatum during development and supports survival
of cultured embryonic DA neurons (6). The structural homology and the similar potency and efficacy of NTN and GDNF in promoting DA neuron
survival (Tables I and II) suggest that GDNF and
NTN may exert redundant trophic influences on
nigral DA neurons (26). To date, there are contrasting reports on the effectiveness of NTN in PD
animal models, probably due to the different experimental conditions adopted (Table II). Recently,
new GDNF-family members, such as neublastin
(NBN) (27), identical to ART, have been cloned.
As with GDNF, protection of nigral DA neurons
has been reported both in vitro and in vivo (27).
However, further investigations are necessary to
clarify whether NTN and NBN/ART might be
considered potential therapeutic agents in PD.
CLASSICAL NTs
All the NTs belonging to the NGF family
bind to the p75 NTR low-affinity receptor, but
their ligand specificity is determined by binding
activating transmembrane receptor tyrosine kinases, the trks. NGF acts through trkA; BDNF
and NT 4/5 act through trkB whereas NT-3 acts
through trkC and, less potently, through trkA and
trkB. In adult CNS, p75NTR receptor, which is related to proteins belonging to the tumor necrosis
receptor-alpha family, appears to be mainly coexpressed with trkA. When not associated with
trk receptors, p75NTR can mediate neuronal death
(28). mRNAs encoding trkB and trkC, the functional high-affinity receptors for BDNF, NT-4/5
and NT-3 respectively, are expressed in the SN
of the adult rat brain, as well as in cultures of developing ventral mesencephalon. The NGF receptor trkA is not expressed in ventral mesencephalic DA neurons and NGF appears to be only a weak trophic factor for DA neurons, most
likely acting through indirect mechanisms.
BDNF
Among the NTs, BDNF is considered an interesting candidate for the development of therapeutic strategies applicable in PD (Table II). BDNF promotes the survival, morphological and biochemical differentiation of DA neurons in fetal
midbrain cultures (29). In addition, BDNF protects DA neurons from the neurotoxic effects of
MPP+ and 6-OHDA (30).
The distribution of BDNF and its high-affinity receptor, trkB, in the nigrostriatal system suggests a critical role of this neurotrophin in the survival of different resident neuronal populations.
FUNCTIONAL NEUROLOGY (16)1 2001
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F. Facchinetti et al.
TrkB mRNA has been found in both cholinergic
and GABAergic striatal interneurons (31). The
expression pattern of BDNF and trkB in the striatum has suggested that BDNF could act both as a
target-derived trophic factor for DA neurons projecting from the SNc, and as an autocrine factor
affecting the survival of neurons within the striatum itself. In the SNc, the mRNAs of both BDNF
and trkB have been detected in DA neurons (32).
The co-expression in nigral DA neurons of BDNF and trkB supports the idea that BDNF can affect neuronal survival by both paracrine and autocrine mechanisms.
Several groups have investigated the survival-promoting effects of BDNF on the nigrostriatal DA pathway and its capacity to prevent behavioral motor asymmetries in animal models of
PD (Table II). In parkinsonian rats, prevention of
nigral cell loss is observed both after supranigral
injection of engineered BDNF secreting fibroblasts (33) and after three-week infusion of BDNF
in the SNc (34). Intrastriatal grafts of engineered
fibroblast- or astrocyte-expressing BDNF partially
prevent nigrostriatal DA degeneration without affecting tyrosine hydroxylase-immunoreactive
(TH-IR) nerve terminals of 6-OHDA-lesioned rats
(35). The effects of BDNF appear to be more transient than those of GDNF, since decrease in rotational behavior and KCl-induced DA release is
observed in rats 1-3 months after the administration of GDNF- but not of BDNF-bridged grafts
(23). Administration of rAAV-expressing BDNF
in the SN of 6-OHDA-lesioned rats reduces amphetamine-induced turning behavior but does not,
in spite of long-term transgene expression, affect
the number of nigral TH-labeled neurons (36).
Thus, although BDNF is as effective as GDNF in
promoting DA neuronal survival, it is not as effective as GDNF in inducing and maintaining the DA
phenotype (Table II).
NT-3 and NT-4/5
NT-3, which acts through the trkC receptor,
has broadly similar effects to BDNF in promoting
50
FUNCTIONAL NEUROLOGY (16)1 2001
the survival and differentiated phenotype of cultured DA neurons. Although BDNF and NT-4/5
are thought to act through the same high-affinity
receptor (trkB), these two NTs have distinct as
well as overlapping actions in vitro. For instance,
NT-4/5 had no effect, in marked contrast to BDNF
and NT-3, on the DA uptake capacity of cultured
mesencephalic neurons (37). In addition, these
factors appear less promising than GDNF (Table
II) in experimental animal models of PD. While
NT-3 and NT-4/5 are nearly as effective as GDNF
in promoting DA neuronal survival, they are less
effective than GDNF in promoting functional and
behavioral recovery (24, 38).
OTHER TROPHIC FACTORS
In addition to GDNF and certain NTs belonging to the classical NT family, basic fibroblast growth factor (bFGF), transforming growth
factor alpha (TGF-alpha), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1),
platelet-derived growth factor-BB (PDGF-BB)
and growth/differentiation factor 5 (GDF5), have
proven to increase DA neuron survival in cultured mesencephalic neurons. As exemplified in
Table II, in experimental animal models of PD,
bFGF and acidic fibroblast growth factor (aFGF)
appear to be moderately effective in promoting
functional and behavioral recovery. However,
bFGF, EGF, PDGF-BB, GDF5 and TGF-alpha
effects are predominantly indirect, as they occur
mainly through the stimulation of glial cell division and release of trophic factors (39).
NTs in PD
In spite of the bulk of preclinical research
conducted so far, the few studies concerning NTs
in human CNS are rather scattered and do not
shed any light on the role of NTs and their receptors in PD (40,41). A number of clinical trials
have either been conducted or are ongoing to
evaluate the safety and the therapeutic benefits of
Neurotrophic factors in the therapy of Parkinson’s disease
NTs in clinical settings associated with loss of
neuronal function, including neurodegenerative
diseases (see Table III). So far, only GDNF has
been tested in PD patients: more specifically,
while a case report showed no benefit and severe
side effects following intracerebroventricular injections of GDNF in a patient with PD (42),
GDNF exposure of fetal DA cells, prior to putaminal implant, was reported to enhance graft survival in two patients with PD (43). These preliminary results raise the possibility that NTs may
perhaps be employed to promote a better graft
survival in the surgical approach to PD treatment.
CONCLUSIONS
Since certain NTs, in particular GDNF and
BDNF, are neuroprotective in animal models of
PD, the rationale for developing therapies involv-
ing the use of native or recombinant NTs is
strong. However, it is not known how closely
neurotoxin-induced lesions mimic the state of
diseased neurons in human PD. While in experimental animals a PD-like syndrome is obtained
through an acute chemical insult (MPTP or 6OHDA), the naturally occurring disease is, in
contrast, a slow and progressive process due to
unknown causes. Thus, benefits observed in animal models with the use of NTs may not necessarily be reproduced in clinical trials. In addition,
beneficial effects could be hampered by potentially occurring side effects consequent to a chronic
treatment (e.g., aberrant neuritic outgrowth, increased function of other responsive neuronal
populations, peripheral effects). Lastly, recent
clinical trials with NTs in other neurodegenerative diseases have been disappointing; e.g.,
GDNF did not appear to be beneficial in amyotrophic lateral sclerosis (ALS) patients and, in
Table III - Overview of the clinical effects of neurotrophic factors in neurodegenerative diseases
Disease
NTs
Trials/clinical
cases
Status/outcome
References
Parkinson’s
disease (PD)
– GDNF(i.c.v.)
– Human fetal
– nigra+GDNF
– Case report
– 2 cases
– Severe side effects
– Enhanced graft
– survival
42
43
Amytrophic
lateral
sclerosis
(ALS)
– GDNF
– BDNF (s.c.)
– BDNF (i.t.)
– BDNF(s.c.high dose)
– CNTF (s.c.)
– Phase II
– Phase III
– Phase II
– Phase II
– Phase II
– Discontinued
– No efficacy
– Ongoing
– Ongoing
– Discontinued (S.E.)
http://www.amgen.com
57
57
57
58
Diabetic
neuropathy
NGF (s.c.)
Phase III
No efficacy
http://www.gene.com
59
Alzheimer’s
disease
NGF
3 cases
? (Hyperalgesia)
60
Constipation
(spinal cord
injury)
NT-3
Phase II
Ongoing
http://www.amgen.com
Immunophilins (p.o.)
Phase I
Ongoing
http://www.amgen.com
PD
ALS
Abbreviations: NTs = neurotrophic factors; GDNF = glial cell line-derived neurotrophic factor; BDNF = brain-derived neurotrophic factor; CNTF = ciliary neurotrophic factor; NGF = nerve growth factor; NT-3 = neurotrophin-3; i.c.v. = intracerebral ventricular; s.c. = subcutaneous; i.t. = intrathecal; P.O. = per os.
FUNCTIONAL NEUROLOGY (16)1 2001
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F. Facchinetti et al.
fact, displayed an array of side effects, while trials conducted with BDNF have not been satisfactory. These failures may, at least in part, be the
consequence of the poor pharmacological properties of NTs (e.g. short in vivo half-lives due to
protein degradation, low blood brain barrier permeability) (44).
On the other hand, to improve CNS delivery
and avoid some of the unwanted effects of systemic administration of NTs, gene therapy techniques have recently been developed and tested
in animal models. The use of recombinant viruses to deliver GDNF or other NTs could avoid repeated invasive intracerebral procedures. Yet,
several improvements are needed in current gene
therapy technology: in safety, cell specificity, stability and possibility of regulation of gene expression.
Neurotrophic factors could also be used in
combination with other therapeutic strategies
such as, for instance, cell replacement interventions. In fact, one limitation of grafting fetal neural tissue or expanded populations of human CNS
progenitor cells into the brain is the relatively
poor survival of the implanted cells. The ability
of GDNF and BDNF to regulate the survival and
differentiation of developing DA neurons can be
used to enhance the success of cerebral grafts
and/or to induce stem cells to phenotypically differentiate into DA neurons. Additionally, GDNF
can be delivered by inserting into the striatum
cells engineered to produce GDNF (45).
A further way to overcome some of the problems linked to the therapeutic use of NTs might
be the employment of low molecular weight compounds, either possessing intrinsic neurotrophic
activity or capable of modulating the synthesis,
release or signalling properties of endogenous
NTs in the nigrostriatal system. Potential candidates include immunophilins (46), and NT
mimetics. To date, however, no data is available
on the possibility of producing low molecular
weight compounds capable of mimicking the activity of GDNF or BDNF. Although this is due to
the relatively poor information as regards the
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FUNCTIONAL NEUROLOGY (16)1 2001
molecular details of their binding to receptors, the
recent reports on NT mimicry strategies conducted in the field of NGF suggest that such an approach is feasible. For example, small cyclic peptides, capable of mimicking NGF β-turn structures that bind specifically to the trkA receptor,
behave as trkA antagonists by competing with
NGF for high affinity binding sites (47), while
non-peptidic small molecule β-turn analogs of an
anti-trkA monoclonal antibody have been reported to function as specific trkA agonists (48). To
circumvent the problem of molecular instability,
D-amino acid peptido-mimetics, more proteaseresistant than L-amino acid peptides and with
longer half-lives, may be soon available (49). In
addition, the development of agents capable of
specifically modulating p75NTR receptor activity,
without affecting the survival promoting functions of trks, may be relevant for the treatment of
neurodegenerative disorders, in which uncontrolled apoptotic processes may be implicated.
Thus, receptor or ligand modeling may give way,
also in the case of BDNF or GDNF, to approaches similar to those mentioned above for NGF,
with the aim of obtaining a fine tuning of neurotrophic activity in PD.
Taken together, the experimental evidence
here reviewed suggests that NTs and their receptors, in particular GDNF and BDNF, may be
important therapeutic targets in PD. Unfortunately, to date, none of the identified NTs is
specific for DA neurons and all of them, on the
other hand, can elicit a wide variety of effects.
Therefore, further knowledge regarding the potential consequences of prolonged exposure to
“therapeutic” doses of NTs is needed. It will also be necessary to develop ways of efficiently
delivering NTs to the brain and/or of locally
stimulating their synthesis or of mimicking
their activity. Hopefully, future research linking
functional genomics with structural molecular
chemistry may allow the design of drugs (e.g.
small molecules, peptide mimetics) capable of
modulating and/or mimicking specific functions
of defined NTs in PD.
Neurotrophic factors in the therapy of Parkinson’s disease
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