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Neuroprotective Strategies in Parkinson’s Disease: An Update on Progress

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In spite of the extensive studies performed on postmortem substantia nigra from Parkinson's disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease confirm these findings. Furthermore, neuroprotection can be afforded in these models with iron chelators, radical scavenger antioxidants, MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calcium channel antagonists and trophic factors. Despite the success obtained with animal models, clinical neuroprotection is much more difficult to accomplish. Although the negative studies obtained with the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vitamin E) may have resulted from an inappropriate choice of drug (selegiline) or an inadequate dose (tocopherol), the niggling problem that still remains is why these drugs, and others, do work in animals while they fail in the clinic. One reason for this may be related to the fact that in normal human brains the number of dopaminergic neurons falls by around 3-5% every decade, while in Parkinson's disease this decline is greater. Brain autopsy studies have shown that by the time the disease is identified, some 70-75% of the dopamine-containing neurons have been lost. More sensitive reliable methods and clinical correlative markers are required to discern between confoundable symptomatic effects versus a possible neuroprotective action of drugs, namely, the ability to delay or forestall disease progression by protecting or rescuing the remaining dopamine neurons or even restoring those that have been lost.A number of other possibilities for the clinical failure of potential neuroprotectants also exist. First, the animal models of Parkinson's disease may not be totally reflective of the disease and, therefore, the chemical pathologies established in the animal models may not cause, or contribute to, the progression of the disease clinically. Second, because of the series of events occurring in neurodegeneration and our ignorance about which of these factors constitutes the primary event in the pathogenic process, a single drug may not be adequate to induce neuroprotection and, as a consequence, use of a cocktail of drugs may be more appropriate. The latter concept receives support from recent complementary DNA (cDNA) microarray gene expression studies, which show the existence of a gene cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and methamphetamine animal models of Parkinson's disease. Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability.
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CNS Drugs 2003; 17 (10): 729-762
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EVIEW
A
RTICLE
1172-7047/03/0010-0729/$30.00/0
Adis Data Information BV 2003. All rights reserved.
Neuroprotective Strategies in
Parkinson’s Disease
An Update on Progress
Silvia Mandel,
1
Edna Gr
¨
unblatt,
2
Peter Riederer,
2
Manfred Gerlach,
2
Yona Levites
1
and Moussa B.H. Youdim
1
1 Department of Pharmacology, Technion – Faculty of Medicine, Eve Topf and US National
Parkinson’s Foundation Centers for Neurodegenerative Diseases, Bruce Rappaport Family
Research Institute, Haifa, Israel
2 Department of Neurochemistry, Bayrische Julius-Maximilians-University of W
¨
urzburg, Clinic
and Polyclinic of Psychiatry and Psychotherapy, W
¨
urzburg, Germany
Contents
Abstract ....................................................................................730
1. Parkinson’s Disease .......................................................................731
1.1 Aetiology ...........................................................................731
1.2 Pathogenesis ........................................................................732
1.2.1 Global Assessment of Dopamine Neurodegeneration Employing Genomic and
Proteomic Analysis .............................................................733
1.2.2 Apoptosis .....................................................................734
2. Neuroprotective Strategies ................................................................735
2.1 Monoamine Oxidase-B Inhibitors ......................................................735
2.1.1 Selegiline (Deprenyl) ...........................................................735
2.1.2 Rasagiline .....................................................................737
2.2 Dopamine Receptor Agonists .........................................................738
2.2.1 Animal Studies .................................................................739
2.2.2 In Vitro Studies .................................................................739
2.2.3 Clinical Neuroprotection with the Dopamine Agonist Pramipexole ..................741
2.2.4 Clinical Implications ............................................................742
2.3 NMDA Receptor Antagonists ..........................................................742
2.3.1 Amantadine ...................................................................743
2.3.2 Memantine ....................................................................743
2.3.3 Riluzole........................................................................743
2.4 Iron Chelators .......................................................................744
2.5 Dietary Antioxidants ..................................................................745
2.5.1 Tocopherol (Vitamin E) .........................................................745
2.5.2 Flavonoids and Polyphenols .....................................................745
2.6 NSAIDs: Cyclo-Oxygenase Inhibitors ...................................................746
2.7 Neuronal Nicotinic Acetylcholine Receptor Agonists ....................................748
2.7.1 Smoking and Parkinson’s Disease ................................................748
2.8 Neurotrophic Factors .................................................................749
3. Future Strategies for Neuroprotection ......................................................749
3.1 Anti-Apoptotic Drugs: Mitochondria, Calcium Channels and Caspases as Potential Targets 749
3.2 Cannabinoids .......................................................................750
3.3 Ecstasy .............................................................................751
3.4 Nitric Oxide Synthase Inhibitors ........................................................751
730 Mandel et al.
3.5 Multidrug (Cocktail) Neuroprotective Therapy ..........................................751
4. Conclusion ..............................................................................752
In spite of the extensive studies performed on postmortem substantia nigra
Abstract
from Parkinson’s disease patients, the aetiology of the disease has not yet been
established. Nevertheless, these studies have demonstrated that, at the time of
death, a cascade of events had been initiated that may contribute to the demise of
the melanin-containing nigro-striatal dopamine neurons. These events include
increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative
stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthe-
sis, abnormal protein folding and aggregation, reduced expression of trophic
factors, depletion of endogenous antioxidants such as reduced glutathione, and
altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of
Parkinson’s disease confirm these findings. Furthermore, neuroprotection can be
afforded in these models with iron chelators, radical scavenger antioxidants,
MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calci-
um channel antagonists and trophic factors.
Despite the success obtained with animal models, clinical neuroprotection is
much more difficult to accomplish. Although the negative studies obtained with
the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vita-
min E) may have resulted from an inappropriate choice of drug (selegiline) or an
inadequate dose (tocopherol), the niggling problem that still remains is why these
drugs, and others, do work in animals while they fail in the clinic. One reason for
this may be related to the fact that in normal human brains the number of
dopaminergic neurons falls by around 3–5% every decade, while in Parkinson’s
disease this decline is greater. Brain autopsy studies have shown that by the time
the disease is identified, some 70–75% of the dopamine-containing neurons have
been lost. More sensitive reliable methods and clinical correlative markers are
required to discern between confoundable symptomatic effects versus a possible
neuroprotective action of drugs, namely, the ability to delay or forestall disease
progression by protecting or rescuing the remaining dopamine neurons or even
restoring those that have been lost.
A number of other possibilities for the clinical failure of potential neuropro-
tectants also exist. First, the animal models of Parkinson’s disease may not be
totally reflective of the disease and, therefore, the chemical pathologies establish-
ed in the animal models may not cause, or contribute to, the progression of the
disease clinically. Second, because of the series of events occurring in neurode-
generation and our ignorance about which of these factors constitutes the primary
event in the pathogenic process, a single drug may not be adequate to induce
neuroprotection and, as a consequence, use of a cocktail of drugs may be more
appropriate. The latter concept receives support from recent complementary DNA
(cDNA) microarray gene expression studies, which show the existence of a gene
cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and
methamphetamine animal models of Parkinson’s disease.
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 731
Even with the advent of powerful new tools such as genomics, proteomics,
brain imaging, gene replacement therapy and knockout animal models, the desired
end result of neuroprotection is still beyond our current capability.
There are currently three therapeutic approaches Many studies have been performed to identify
to Parkinson’s disease: (i) symptomatic; (ii)
gene mutations in Parkinson’s disease, and some
neuroprotective; and (iii) restorative. In Parkinson’s
candidate genes, including superoxide dismutase
disease, disruption of the nigrostriatal pathway leads
(SOD) and catalase, have been excluded.
[6]
The first
to dopamine deficiency, particularly in the putamen.
gene identified as being directly involved in the
This forms the basis for dopamine replacement strat-
familial form of Parkinson’s disease was SNCA,
egies with levodopa and dopamine receptor ago-
which codes for a presynaptic protein (α-synuclein)
nists. Although these treatments can provide dra-
that is defective in the disease,
[7,8]
though its precise
matic initial improvement, their effects are often
function is unknown. Mutated α-synuclein tends to
short lived, and adverse motor and mental reactions
have increased aggregability, as supported by in
significantly limit therapy.
[1]
Furthermore, neither
vitro studies.
[9]
The relevance of α-synuclein to the
levodopa nor other antiparkinsonian drugs are capa-
great majority of cases of sporadic Parkinson’s dis-
ble of arresting the progression of the disease and
ease is related to the observation that it is one of the
the deterioration of the nigrostriatal system. Thus,
components of Lewy bodies.
[10]
This finding led to
other approaches for Parkinson’s disease are clearly
the suggestion that aggregated, misfolded α-
needed. Neuroprotection can be defined as an inter-
synuclein may accumulate and interfere with the
vention that slows or stops neuronal degeneration
ubiquitin-proteasome system that is responsible for
and aims to interfere with the basic pathogenetic
the clearance of misfolded and damaged proteins.
[11]
mechanism of nigral cell death. Neurorestoration is
However, no cases of idiopathic Parkinson’s disease
another category of potential treatment for Parkin-
presenting a mutation in α-synuclein have so far
son’s disease and involves placement of new cells
been reported.
such as fetal nigral neurons into the striatum of
Recently, a gene called Parkin, encoding a pro-
patients with the disease. This approach has the
tein with structural similarity to the ubiquitin family
theoretical advantage of replacing damaged neurons
of proteins, was found to cause a juvenile autosomal
with functioning cells but in practice has yielded
recessive form of Parkinson’s disease.
[12]
The Parkin
only modest improvement.
[2-5]
gene encodes an ‘E3’ ubiquitin ligase, functioning
In this article, the current state of neuroprotection
with E2 proteins to ubiquitinate proteins for
and future drug strategies are reviewed. Restorative
proteasomal recognition and metabolism.
[13]
How-
therapies such as dopaminergic cell transplants and
ever, none of the aforementioned genes was shown
virally mediated delivery of trophic factors, or spe-
to play a common pathogenic role in idiopathic
cific brain stimulation, will not be discussed.
Parkinson’s disease, since no mutations have been
found in the sporadic form of the disease,
[14]
which
1. Parkinson’s Disease
constitutes >95% of the individuals affected.
The evidence points to a crucial implication of
1.1 Aetiology
protein misfolding and aggregation into protein in-
clusions (Lewy bodies), containing α-synuclein and
Although the underlying cause of Parkinson’s
ubiquitin, not only in familial, but also in sporadic
disease is still unknown, a number of potential con-
Parkinson’s disease. The ubiquitin-proteasome sys-
tributing factors – including genetic aberrations and
tem is of central importance in the degradation of
endogenous or environmentally derived neurotoxins
have been proposed. normal and damaged proteins. All the identified
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
732 Mandel et al.
gene mutations in familial Parkinson’s disease cases necrosis and/or apoptosis (see section 1.2.2). The
are capable of impairing the activity of this sys-
current hypothesis concerning the pathogenesis of
tem.
[15]
In addition, reduction in the activity of the
Parkinson’s disease holds that there is an ongoing
26/20S subunit of the proteasome system has been
selective oxidative stress and excessive iron ac-
described in the substantia nigra pars compacta of
cumulation that expresses itself with biochemical
sporadic Parkinson’s disease.
[16]
Inhibition of the
alterations compatible with this state.
[17-23]
Addition-
ubiquitin-proteasome system is directly linked to the
al mechanisms participating in the cascade of events
release of cytochrome C from mitochondria and
include inflammatory processes (probably via reac-
activation of the caspase cascade leading to apopto-
tive microglia), glutamatergic neurotoxicity, mito-
sis and cell death. It is thus clear that the majority of
chondrial (complex I deficiency) and ubiquitin-
cases of Parkinson’s disease cannot be attributed to
proteasome system dysfunction, and decline in
a single cause but most likely are a result of an
growth factor levels,
[21,24]
as summarised in figure 1.
interaction between several genetic or environmen-
Much of our knowledge about dopaminergic
tal factors, acting independently or in conjunction.
neurodegeneration has come from studies with two
neurotoxins that produce models for oxidative stress
1.2 Pathogenesis
and parkinsonism syndrome in rodents, primates
and other species. Both neurotoxins, 6-hydroxy-
Although the underlying cause of idiopathic
dopamine (6-OHDA)
[25,26]
and 1-methyl-4-phenyl-
Parkinson’s disease is unknown and, apparently,
1,2,3,6-tetrahydropyridine (MPTP),
[27-29]
are known
inherited and sporadic forms of Parkinson’s disease
to impair mitochondrial complex I activity and
involve distinct aetiology, there is substantial infor-
cause degeneration of nigrostriatal dopamine neu-
mation showing that both familial and sporadic
rons, with subsequent loss of striatal dopamine.
Parkinson’s disease share common biochemical pro-
The ability of the antiparkinsonian drug
cesses in the degeneration and final death of the
dopaminergic neurons of the substantia nigra, by selegiline (deprenyl), an irreversible monoamine ox-
NMDA antagonists
Ca
2+
chelators
Growth
factors
Induction of
catalase
NOS inhibitors
Radical scavengers,
iron chelators
Release of
ferritin iron
Dopamine
agonists (e.g.
apomorphine,
pramipexole)
Reduction in ubiquitin-
proteasome system
Neuronal
death
Protein
aggregation
Bioenergetic drugs
Anti-apoptotic drugs
Iron accumulation, oxidative stress and inflammation
Nitric oxideGlutamate/aspartate excitotoxicity
Neurotoxins
Impaired cellular respiration
Fig. 1. Biochemical events associated with neurodegeneration of dopaminergic neurons in Parkinson’s disease. Dotted lines indicate
potential tar
g
ets for dru
g
-induced neuroprotection. NOS = nitric oxide s
y
nthase.
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 733
idase (MAO)-B inhibitor, to prevent MPTP-induced We have recently employed cDNA microarray,
parkinsonism in mice and nonhuman primates was
for the first time, at early and late stages of MPTP
the first example of neuroprotection for Parkinson’s
neurodegeneration, where the viability of dopamine
disease.
[30]
The mechanism of this process has been
neurons is seriously compromised. This technique
explained by the inhibition of MAO-B by selegiline,
has shed light on the complexity of the biochemical
thus preventing the metabolism of the neurotoxin to
processes (figure 2) described in neurodegenera-
the reactive 1-methyl-4-phenylpyridium ion
tion.
[24,48,49]
In this study, MPTP caused an elevation
(MPP+) and the formation of hydrogen peroxide.
in the expression of >50 genes related to oxidative
However, this explanation appears to be too simple,
stress, inflammation, glutamate excitotoxicity and
as selegiline was shown to prevent, as well as to
neurotrophic factor pathways, as well as in cell cycle
rescue cultured nigral neurons from, the induced
regulators and apoptotic and signal transduction
oxidative damage caused by the reactive metabolite
molecules. Most of the gene alterations were pre-
MPP+.
[31]
Moreover, other drugs not having MAO-
vented by the dopamine agonist and radical scaven-
B inhibitory action can also exert neuroprotection in
ger R-apomorphine.
this model. So far, iron chelators (e.g. deferoxamine
More recently, temporal profiling of metham-
[desferrioxamine]),
[32-35]
antioxidants (tocopherol
phetamine-induced gene expression in rat cortex
[vitamin E]),
[33,36,37]
the dopamine agonists apomor-
demonstrated early elevation of transcription fac-
phine
[38-40]
and bromocriptine,
[41]
glutathione ana-
tors, including members of the jun family, while a
logues
[42]
and a nitric oxide synthase (NOS) inhibi-
delayed pattern showed upregulation of trophic fac-
tor (7-nitro-indazole [7NI] but not N-nitro-L-argi-
tors, cell death and DNA repair, similar to what has
nine methylester [L-NAME])
[43,44]
have been
been found in the MPTP model.
[50]
Additionally,
described as having the same effect.
alterations in messenger RNA (mRNA) related to
Although at first glance there does not seem to be
oxidative stress, inflammation and neurotransmitter
a common mechanistic feature among these com-
receptor classes were also observed. However, the
pounds, a closer examination reveals that they all
major affected area in parkinsonism, namely the
converge to a possible participation of hydroxyl
substantia nigra, was not examined. A more recent
radicals and iron in MPTP-induced neurodegenera-
study has focused on gene changes in the midbrain,
tion. Still, many of these drugs have not shown
containing the substantia nigra, of mice intoxicated
neuroprotection in patients with Parkinson’s disease
with methamphetamine. The authors reported a ma-
(see section 2), which might indicate the existence
jor elevation in energy metabolism-related genes
of more intricate processes than in the animal mod-
such as cytochrome C oxidase, as well as a reduction
els. Therefore, treatment with a cocktail of drugs
in a glycolytic pathway mRNA.
[51]
Similar changes
that possess different neuroprotective properties
were also described in the MPTP model, where a
may open alternative neuroprotective avenues.
decrease in the glucose transporter was observed.
These results are in keeping with a recent finding in
1.2.1 Global Assessment of Dopamine
patients with Parkinson’s disease using positron
Neurodegeneration Employing Genomic and
emission tomography (PET) analysis, demonstrat-
Proteomic Analysis
ing a decrease in glucose uptake into the substantia
The technique of complementary DNA (cDNA)
nigra.
[52]
expression array is being extensively used to study
Analysis of gene expression in the striatum of
global changes in gene expression in disease, in
rats treated for 2 months with 6-OHDA revealed
model systems and in response to drug treat-
alterations in a number of transacting factors as well
ment.
[45-47]
These techniques may lead to a more
as transcriptional and cell cycle regulators. Addi-
profound understanding of the disease pathology
tionally, 6-OHDA-induced denervation of the stri-
and the development of more specific and effective
atum results in an impairment in the dopamine/
drugs.
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
734 Mandel et al.
Induction
of catalase
Neurotoxins
Oxidative stress
Impaired cellular
respiration
Glutamate/aspartate
excitotoxicity
Nitric oxide
Cell cycle
regulators
Apoptosis
Cell death
Heat-shock
protein
Cell cycle
arrest
before mitosis
Dysregulated
mitochondrial
function
Inflammation
Fe
2+
Genetic and
neurotoxic events
Reduced glucose
metabolism
Decrease in
transferrin receptor
Growth factors
Fig. 2. Current hypothesis for the neurodegeneration cascade of events in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model
of Parkinsons disease, as emerged from complementary DNA (cDNA) microarray analysis (reproduced from Gr
¨
unblatt et al.,
[49]
with
permission from Blackwell Publishin
g)
. Dashed lines indicate inhibition; solid lines indicate induction.
protein kinase A/cyclin-dependent kinase-5/protein type, dose and administration regimen, are still
needed.
phosphatases cascade, which regulates the state of
phosphorylation and activity of DARPP-32 (dop-
1.2.2 Apoptosis
amine and cAMP-regulated phosphoprotein of M[r]
Apoptosis is a highly conserved energy-requiring
32 000) and of various downstream effectors includ-
programme for noninflammatory cell death that is
ing neurotransmitters, glutamate AMPA and
important in both normal physiology and disease.
NMDA receptors, voltage-gated channels and tran-
Apoptosis is necessary for normal development, but
scription factors.
[53]
it also occurs in many acute and chronic pathologi-
The previously reported biochemical evidence in
cal conditions,
[54,55]
as seems to be the case in neuro-
idiopathic Parkinson’s disease, together with the
degenerative disorders, in concurrence with other
gene array data, has largely extended the view of the
forms of cell death such as necrosis. The potential
cascade of gene events associated with MPTP-,
involvement of apoptosis in Parkinson’s disease,
6-OHDA- and methamphetamine-induced dopa-
although controversial, has been well discussed in
minergic neurodegeneration. One important aspect
the recent review by Blum et al.
[56]
The apoptotic
to consider relating to the power of genomics and
features described in the substantia nigra of patients
proteomics is the extent of homology existing be-
with Parkinson’s disease include the increased 3-
tween the various models and idiopathic Parkin-
end terminal staining of DNA (terminal deoxy-
son’s disease and whether such models are truly
nucleotide transferase-dUTP nick-end labelling
representative of the disease. Implementation of
[TUNEL] method) as an index of DNA fragmenta-
large-scale protein microcharacterisation in con-
tion, chromatin condensation, irregular nuclear mor-
junction with genomic tools promises the discovery phology and the presence of apoptotic cell bodies.
of biomarkers for early detection and diagnosis, as
Other studies have questioned the presence of
well as novel protein-based drug targets. Despite the
apoptotic cells in the substantia nigra pars compacta
encouraging data obtained with the different mod-
in Parkinson’s disease, given that the morphological
els, well designed studies, with regard to neurotoxin
and biochemical evidences are insufficient and con-
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 735
tradictory to formally indict apoptosis as the mecha- animal models and the lack of availability of suita-
ble neuroprotective models.
nism of neuronal cell death.
[56,57]
The inconclusive
evidence may be a result of several factors. First,
This part of the review focuses on the most
Parkinson’s disease and other neurodegenerative
pertinent neuroprotective interventions as reviewed
diseases are diseases of aging, taking place over
from both animal and clinical experimental studies.
years or decades, while a considerable number of
2.1 Monoamine Oxidase-B Inhibitors
experimental models thus far display apoptotic cell
death features within a short time span. Therefore, it
MAO catalyses the oxidative deamination of
may be extremely hard to identify this morphology
monoamine neurotransmitters and neuromodulators
in a chronic degenerative disease. Second, perform-
such as dopamine, noradrenaline (norepinephrine),
ing ultrastructural studies on human postmortem
serotonin and β-phenylethylamine, as well as some
tissue to a high degree of accuracy is extremely
exogenous bioactive monoamines. Two types of
difficult, since many variables related to the quality
MAO exist in mammalian tissues – MAO-A and
of tissue preservation need to be controlled. The
MAO-B – with different substrate and inhibitor
final demonstration of apoptotic-mediated cell death
specificity.
[58]
MAO-A preferentially deaminates se-
will depend on the availability of a drug to inhibit
rotonin and is sensitive to selective inhibitors, such
one or more pathways involved in this phenomenon,
as clorgiline (clorgyline). MAO-B preferentially de-
to assess whether the progression of Parkinson’s
aminates β-phenylethylamine and is sensitive to
disease could be delayed or halted.
MAO-B inhibitors, such as selegiline and rasagi-
The above-described findings indicate that the
line.
[59]
Inhibitors of MAO-A have been proven to
familial and sporadic forms of Parkinson’s disease
be effective antidepressant and antiparkinsonian
involve different aetiological factors, although they
drugs, whereas MAO-B inhibitors are considered
appear to share a common biochemical pathology. It
specific for the treatment of Parkinson’s disease.
is still a matter of debate whether the final process
MAO-B constitutes about 80% of the total MAO
leading to the demise of the dopaminergic neurons
activity in the human brain
[60,61]
and is the predomi-
occurs via apoptosis or necrosis. No matter which of
nant form of the enzyme in the striatum.
[17]
them plays a major role in neurodegeneration, the
2.1.1 Selegiline (Deprenyl)
interference with one or more of the metabolic path-
Selegiline (phenyl-isopropyl-methyl-propargy-
ways may help to prevent or slow down neuronal
lamine) was synthesised by Z. Ecseri, a chemist of
death and the consequent clinical symptoms.
the Chinoin Pharmaceutical Works in Budapest. The
first paper regarding the pharmacological activity of
2. Neuroprotective Strategies
the drug was published in 1965 by Knoll and col-
leagues.
[62]
Selegiline irreversibly inhibits MAO-B,
and its (
)-isomer is a more potent inhibitor than its
Neuroprotective strategies are mainly based on
(+)-enantiomer.
[63]
the accumulated evidence concerning the pathogen-
esis of Parkinson’s disease. Most of the neuropro-
Selegiline was originally introduced by a Hun-
tective experimental studies have been effectively
garian scientist
[64]
as a psychoenergetic agent and
conducted in cellular lines or animal models of the
was suggested later, in 1975 by Birkmayer et al.,
[65]
disease. Despite the success in these models, clinical
for patients with advanced Parkinson’s disease com-
neuroprotection is much more difficult to accom-
plicated by response fluctuations. Selegiline itself
plish. One reason might be related to the fact that the
has mild antiparkinsonian activity, smoothes out
animal models do not accurately reproduce the path-
‘on/off’ fluctuations and allows a reduction in levo-
ogenesis of the disease; another might be the slow
dopa dosage of approximately 30%.
[66]
Patients with
progressive nature of Parkinson’s disease compared
early morning akinesia and mild ‘wearing off’ type
with the acute neurotoxicity encountered in the
fluctuations seem most likely to benefit.
[67]
Other
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
736 Mandel et al.
beneficial effects include a mild antidepressant ac- line, aminoindan, was shown to be a poor inhibitor
tion.
[67-69]
Birkmayer and colleagues
[70]
were the
of dopamine uptake.
first to indicate a possible neuroprotective effect of
Finally, selegiline, similar to rasagiline, may in-
selegiline, based on a retrospective evaluation of 7
duce neuroprotection and neuronal plasticity by a
years of clinical application of the drug.
mechanism(s) independent of its ability to inhibit
The neuroprotective action of selegiline in neu-
MAO-B, probably involving expression of anti-
ronal cell cultures and animal models is multifold in
apoptotic molecules, neurotrophic factors and mito-
nature. There are at least five accepted mechanisms
chondrial membrane potential maintenance.
[82]
by which selegiline could prevent neurodegenera-
In vitro studies have shown that selegiline is able
tion.
to protect dopaminergic SH-SY5Y cells from apop-
First, selegiline may decrease free radical forma-
tosis induced by N-methyl-R-salsolinol in a dose-
tion (generation of hydrogen peroxide) arising from
dependent manner, suggesting that it may initiate
the normal metabolism of biogenic amines, mainly
intracellular processes to repress the apoptotic cell
dopamine, by inhibition of MAO-B in the CNS.
[71]
death programme.
[83,84]
Similarly, selegiline was
In the presence of an Fe
2+
ion, hydrogen peroxide is
found to increase the synthesis of anti-apoptotic bcl-
metabolised through the Fenton reaction to a
2 and bcl-xL proteins and to reduce the apoptotic
hydroxyl radical, which causes membrane and DNA
protein bax.
[82]
Furthermore, treatment with
destruction. It is well known that MAO-B activity
selegiline for 24 hours increased the content of
increases with age, which may lead to an increase in
nerve growth factor (NGF), brain-derived neurotro-
hydrogen peroxide formation.
[72,73]
In addition to the
phic factor (BDNF) and glia-derived neurotrophic
oxidative stress caused by the age-dependent in-
factor (GDNF) in the conditioned medium of cul-
crease of MAO-B activity, further reactions between
tured mouse astrocytes, suggesting the involvement
endogenous amines and aldehydes formed by
of endogenous neurotrophic factors in the neuropro-
MAO-B can also play a role in neurodegenera-
tective action of the drug.
[85]
tion.
[74]
The neuroprotective properties of selegiline,
Second, according to some authors, selegiline
which may influence the progress of Parkinson’s
may increase the free radical scavenging capacity of
disease, have been extensively investigated and are
the brain by elevation of SOD and catalase in the
summarised in table I. Despite the extensive labora-
striatum
[75-77]
and extra brain tissues, depending on
tory studies supporting the notion that selegiline
the sex and age of the animal.
[77]
However, other
(and tocopherol; see section 2.5.1) possess neuro-
investigators have not observed an increase in SOD
protective attributes, no conclusive results have
function.
[78]
been obtained in clinical trials. The Deprenyl and
Third, as a result of MAO-B inhibition, selegiline
Tocopherol Antioxidant Therapy of Parkinson’s
may prevent the activation of environmental pretox-
Disease (DATATOP)
[86]
and Sinemet-Deprenyl-
ins.
[79]
Parlodel (SINDEPAR)
[87]
prospective, double-blind
studies showed that selegiline-treated patients ex-
Fourth, as a result of inhibiting nerve ending
hibited a delay in the onset of disability necessitat-
uptake, selegiline and its metabolites ([
]-metham-
ing levodopa therapy or had significantly less deteri-
phetamine and [
]-amphetamine) may prevent up-
oration than placebo-treated individuals, respective-
take of endogenous neurotoxins.
[80]
However, this
ly. Despite the encouraging results, there were
may not necessarily be the case, since the selective
concerns as to whether the apparent neuroprotective
MAO-B inhibitor rasagiline, which possesses a sim-
action of selegiline might have been confounded or
ilar structure to selegiline, has low uptake inhibitory
masked by long-duration symptomatic effects due to
activity yet shares all the neuroprotective activity of
MAO-B inhibition.
selegiline.
[81]
Furthermore, the metabolite of rasagi-
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 737
Table I. Evidence for the neuroprotective properties of the monoamine oxidase (MAO)-B inhibitor selegiline
Properties References
Protection against neurotoxins
Selegiline protected against the neurotoxicity induced by MPTP by inhibition of the conversion of MPTP to 88
MPP+
In animal models, selegiline protected against the toxic damage induced by MPTP, 6-OHDA, haloperidol and 71,89-91
the noradrenergic neurotoxin DSP-4
Protection against free radical formation
Selegiline inhibited dopamine metabolism by MAO-B, which generates hydrogen peroxide 92
Selegiline inhibited hydroxyl radical formation induced by MPP+ or the 2-methyl analogue of MPTP 93,94
Long-term treatment with selegiline increased activities of SOD and catalase in the striatum of animals 95
Effects on neurotrophic factors
Treatment of cultured mouse astrocytes with selegiline upregulated NGF, BDNF and GDNF synthesis 85
Protection against apoptosis
Selegiline and other propargylamines protected dopaminergic neurons from apoptotic cell death 83,96
Effects on longevity and in Parkinson’s disease
Selegiline has been reported to induce longevity in rats 97,98
Selegiline increases life expectancy in patients with Parkinsons disease 99-101
Selegiline delays the need for levodopa in patients newly diagnosed with Parkinsons disease (levodopa-sparing 86
effect)
6-OHDA = 6-hydroxydopamine; BDNF = brain-derived neurotrophic factor; DSP-4 = N(2-chloroethyl)-N-ethyl-2-bromobenzylamine; GDNF
= glia-derived neurotrophic factor; MPP+ = 1-methyl-4-phenylpyridinium; MPTP = N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NGF =
nerve growth factor; SOD = superoxide dismutase.
2.1.2 Rasagiline
tion of MAO-B.
[104,107]
Western blot measurements
have shown that both drugs prevent the decrease in
Rasagiline (N-propargyl-1[R]-aminoindan) is a
bcl-2 and Cu/Zn-SOD1 that occurs upon serum and
propargylamine-related compound with a similar
NGF withdrawal in partially neuronally differentiat-
structure to selegiline; it is a selective irreversible
ed PC12 cells.
[108]
Furthermore, long-term treatment
inhibitor of MAO-B. In vitro and in vivo studies
with rasagiline induced the increase of SOD and
have demonstrated that rasagiline is up to ten times
catalase in brain and other tissues of rats.
[76]
Using
more active than selegiline as an MAO-B inhibi-
neuronal cell lines, rasagiline was shown to act
tor
[59]
and neuroprotective agent.
[83]
15–20% more effectively as a neuronal survival
The neuroprotective activity of rasagiline has
agent than selegiline, increasing the survival of dop-
been examined in several in vitro, in vivo and cell
aminergic neurons with no statistically significant
culture studies.
[59,102-104]
Rasagiline was found to
increase in the survival of GABAergic neurons.
[109]
prevent the cell death caused by apoptosis, to pre-
Rasagiline, unlike selegiline, is not derived from
serve the mitochondrial membrane potential (∆Ψm),
an amphetamine moiety or metabolised to amphet-
to completely suppress the activation of caspase 3
amine. This is considered a great advantage, given
and DNA fragmentation,
[105]
and to prevent toxin-
that the amphetamine metabolite of selegiline may
induced translocation of the proapoptotic glycer-
interfere with its neuroprotective action in vivo, as
aldehyde-3-phosphate dehydrogenase (GAPDH)
suggested by Oh et al.
[110]
Indeed, a recent study
[111]
into the nucleus
[106]
in neuroblastoma SH-SY5Y
has clearly shown that, while the methamphetamine
cells. In addition, TV1022, the optical (S)-isomer of
metabolite of selegiline interferes with the
rasagiline, which is devoid of MAO-A and -B inhib-
neuroprotective anti-apoptotic actions of selegiline
itory action, has shown similar neuroprotective,
in PC12 cells, the metabolite of rasagiline, ami-
anti-apoptotic activity to rasagiline, suggesting that
the neuroprotective effects are not related to inhibi- noindan, was devoid of such properties. The broad
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
738 Mandel et al.
range of neuroprotective activities of rasagiline is rasagiline-treated patients significantly improved at
both doses, whereas placebo-treated patients wors-
summarised in table II.
ened over the course of the study.
[118]
A more profound neuroprotective action of
Furthermore, very recent findings demonstrated
rasagiline recently described is its ability to process
that patients with early Parkinson’s disease who
amyloid precursor protein by inducing the release of
were treated with rasagiline for 12 months showed a
the neuroprotective/neurotrophic soluble amyloid
lesser decline in their motor function and activity of
precursor protein α.
[114]
This may be related to its
daily life than patients whose active treatment was
ability to increase bcl-2 and bcl-xL mRNA and
delayed for 6 months.
[119]
These results cannot be
protein levels
[115]
in cell culture and the activation of
explained by a purely symptomatic effect of
signal transduction pathways, involving mitogen-
rasagiline. The potential disease-modifying effect of
activated extracellular regulatory kinases 1 and 2
rasagiline warrants further examination. The ami-
(ERK1/ERK2).
[113]
It is now apparent that the
noindan metabolite of rasagiline, which also has
MAO-B inhibitory action of rasagiline is not respon-
neuroprotective activity, unlike the metabolites of
sible for its neuroprotective activity, since its optical
selegiline, may ultimately contribute to the action of
S-isomer, which possesses very little MAO inhibito-
rasagiline.
ry activity, has a similar mechanism of neuroprotec-
tive action.
[112]
We have shown that the propargyl
2.2 Dopamine Receptor Agonists
moiety in this drug is responsible for this intrinsic
neuroprotective activity.
[114,116]
Dopamine receptor agonists act directly on
In a clinical trial, rasagiline as adjunctive therapy
striatal dopamine receptors. Unlike levodopa, dop-
to levodopa produced an improvement in total Uni-
amine agonists do not require oxidative metabolic
fied Parkinson’s Disease Rating Scale (UPDRS)
conversion and hence do not generate potentially
scores at 12 weeks’ treatment, which persisted in the
toxic free radical metabolites.
[120]
The iron-induced
postdrug follow-up period at 6 weeks (week 18) for
oxidative stress within the dopaminergic neurons of
patients receiving rasagiline but not those receiving
the substantia nigra pars compacta is hypothesised
placebo.
[117]
Phase III studies in patients with early
to play a major role in the pathogenesis of Parkin-
Parkinson’s disease, who were treated with 1 or 2
son’s disease.
[20,22,121]
Findings from clinical, animal
mg/day of rasagiline for 26 weeks, showed that
and cell culture studies suggest potential neuropro-
motor scores and quality-of-life measures in
tective properties of dopamine agonists by scaveng-
Table II. Neuroprotective properties of the irreversible monoamine oxidase-B inhibitor rasagiline (reproduced from Youdim et al.,
[112]
copyright 2001 New York Academy of Sciences, USA, with permission)
Increases superoxide dismutase, catalase and bcl-2 activities by transcriptional and translational means in PC12 cells and rats (brain,
heart and kidney)
Prevents peroxynitrite-induced activation of caspase 3
Prevents peroxynitrite-induced DNA lathering
Prevents glutamate- and NMDA-induced neurotoxicity in hippocampal and cortical cell cultures
Prevents peroxynitrite- and salsolinol-induced falls in mitochondrial membrane potential
Protects against peroxynitrite-induced apoptosis
Neuroprotective in closed head injury in mice
Protects against cell death induced by ischaemia and glucose deprivation in PC12 cells
Prevents neurotoxicity induced by MPTP (mice) and 6-hydroxydopamine (PC12 cells and rats)
Increases survival of dopaminergic neurons in vitro
Neuroprotective in models of motor and cognition disorders
Processes APP by inducing the release of the neuroprotective/neurotrophic soluble APPα in PC12 and SH-SY5Y neuroblastoma
cells
[113]
APP = amyloid precursor protein; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 739
ing free radicals,
[122-124]
chelating free iron,
[125]
re- HVA (figure 3 [a]) and in the levels of reduced
ducing dopamine catabolism
[126]
and increasing ex- glutathione, induced by MPTP in mice.
[40]
The
pression of anti-apoptotic genes
[127]
and neuroprotection induced by R-apomorphine is at-
neurotrophic factors.
[128-130]
tributed not only to action at dopamine receptors but
also to its radical-scavenging and iron-chelating fea-
2.2.1 Animal Studies
tures.
[122,138,139]
Apomorphine is a catechol-derived
Hall et al.
[131]
reported that the dopamine D
2
/D
3 compound that is easily oxidisable and can therefore
receptor agonist pramipexole (1 mg/kg orally twice
react with reactive oxygen species (for a review, see
daily for 28 days) significantly prevented tyrosine
Gassen and Youdim
[140]
).
hydroxylase (TH)-positive neuronal loss induced by
The first global assessment of the gene cascade of
forebrain ischaemia in male gerbils or by metham-
events occurring in the nigrostriatal pathway in
phetamine in mice. These findings are in accordance
MPTP-induced neurodegeneration, employing
with a previous study,
[132]
in which bromocriptine,
cDNA microarray, has recently been reported.
[49]
an ergoline selective D
2
receptor agonist, conferred
This study revealed the involvement of different
protection against methamphetamine-induced neu-
genes related to oxidative stress (cytochrome P450),
rotoxicity towards dopaminergic neurons in mice.
inflammation (interleukin [IL]-1, IL-6, tumour ne-
Similarly, R-apomorphine, a D
1
/D
2
receptor agonist
crosis factor [TNF]-α), protective cytokines (IL-10),
acting both pre- and postsynaptically,
[133]
was
glutamate receptors (NMDA but not AMPA recep-
shown to prevent striatal dopamine, 3,4-dihydrox-
tors), neurotrophic factors (GDNF, epidermal
yphenylacetic acid (DOPAC) and homovanillic acid
growth factor), NOS and transferrin receptor, as
(HVA) depletion in mice as well as TH-activity
well as cell cycle regulators and signal transduction
reduction induced by methamphetamine.
[134]
In this
factors. R-apomorphine prevented or attenuated the
study, administration of the dopamine antagonist
expression of the majority of gene alterations.
haloperidol in combination with R-apomorphine did
The S-enantiomer of apomorphine, which is de-
not prevent the protective effect of R-apomorphine,
void of dopamine receptor agonism, prevented dop-
suggesting a dopamine receptor-independent neuro-
amine depletion at a dosage of 1 mg/kg/day (figure 3
protective effect of the dopamine agonist. However,
[b]) and the elevated dopamine turnover and TH
determination of dopaminergic neuron cell number
activity induced by MPTP to a similar extent as R-
in the substantia nigra of R-apomorphine-treated
apomorphine, except that it was ten times more
mice is further required to ascertain full neuropro-
effective than the R-enantiomer.
[40]
Gr
¨
unblatt et
tection.
al.
[49]
recently demonstrated that both R-apomor-
Ropinirole, a non-ergoline D
2
/D
3
receptor ago-
phine and S-apomorphine prevented the increase in
nist,
[135]
and pramipexole
[136]
were reported to exert
TNFα-induced protein, GDNF and cyclin B2
neuroprotective effects on 6-OHDA- or MPTP-in-
mRNAs induced by MPTP in the substantia nigra.
duced striatal dopamine reduction, dopaminergic
The fact that both enantiomers of apomorphine pre-
neuronal loss and lipid peroxidation, respectively.
vented the effects of MPTP on the expression of
The neuroprotective actions of pramipexole have
these genes suggests that other pharmacological
been attributed not only to dopamine receptor stimu-
properties, besides dopamine receptor agonism, may
lation but also to its radical-scavenging activity.
[128]
play a role in the neuroprotective effects of the drug.
However, the scavenging activity of ropinirole is
lower than other dopamine agonists such as bromo- 2.2.2 In Vitro Studies
criptine and pergolide,
[137]
suggesting that other
Studies employing either cell line cultures or
properties might mediate neuroprotection.
primary neuronal cultures have shown direct
Gr
¨
unblatt et al.
[39]
showed that R-apomorphine neuroprotective properties of dopamine agonists.
(10 mg/kg) significantly prevented the decline in Preincubation with bromocriptine provided neuro-
levels of dopamine and its metabolites DOPAC and protection against glutamate or levodopa-induced
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
740 Mandel et al.
a
0
20
40
60
80
100
120
140
Dopamine and DOPAC
(% of control)
Control Apo Apo +
MPTP
R-apomorphine 5 mg/kg/day
R-apomorphine 10 mg/kg/day
MPTP
***
*
Control Apo
*
*
MPTP
Apo +
MPTP
Dopamine
DOPAC
Control
S-apomorphine
MPTP
S-apomorphine + MPTP
S-apomorphine (mg/kg/day)
Dopamine (% of control)
DOPAC (% of control)
0
20
40
60
80
100
120
140
160
0
20
40
60
80
100
120
140
160
180
b
***
*
*
0.5
*
*
1
***
2
**
*
0.5 12
***
Fig. 3. Effect of S- and R-apomorphine on striatal catecholamine content of C57/BL mice after exposure to the neurotoxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The mice were injected with (a) R-apomorphine (5 or 10 mg/kg) or (b) S-apomor-
phine (0.5, 1 or 2 mg/kg) followed by a dose of MPTP (24 mg/kg) for 5 days. Controls received saline only. Absolute dopamine and
3,4-dihydroxyphenylacetic acid (DOPAC) levels in control, untreated mice are 33 ± 2.17 and 1.9 ± 0.16 pmol/mg tissue, respectively. The
results represent the mean ± standard error of the mean (n = 68 mice) of a representative experiment ([b] reproduced from Gr
¨
unblatt et
al.,
[40]
with permission from Blackwell Publishing). Apo = apomorphine; ANOVA: * p < 0.05, ** p < 0.01, *** p < 0.001 vs control; p < 0.05,
p < 0.01 vs MPTP.
neurotoxicity in cultured rat mesencephalic neu- still evident in the presence of selective D
2
or D
3
antagonists. Regardless of the discrepancies that
rons.
[141,142]
This effect was blocked by a D
2
ant-
exist between the different studies, which may re-
agonist, indicating the participation of dopamine
flect differences in cell systems or incubation condi-
receptor agonistic action in the protective effect.
tions, there has been an increasing body of evidence
Similarly, the prevention of levodopa-induced loss
in the last years suggesting that dopamine agonists
of cultured mesencephalic neurons by pramipexole
may exert neuroprotection through a combination of
was attenuated by a selective D
3
antagonist,
[143]
several attributes, including antioxidant effects and
whereas in this study bromocriptine and pergolide
dopamine receptor activation.
[24]
did not provide any protection. In contrast to these
studies, the protective effect of pramipexole against In previous studies, R-apomorphine was shown
levodopa-,
[127]
dopamine-, 6-OHDA- or hydrogen to exert the greatest protection against 6-OHDA-
peroxide-induced
[144]
cytotoxicity in the Mes23.5 and hydrogen peroxide-induced PC12 cell death in
dopaminergic cell line has also been reported to be culture,
[38]
when compared with the other dopamine
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 741
2.2.3 Clinical Neuroprotection with the Dopamine
agonists bromocriptine, lisuride and pergolide. Sim-
Agonist Pramipexole
ilarly, S-apomorphine, which is inactive at dop-
As discussed in sections 2.2.1 and 2.2.2, in vitro
amine receptors, was equally potent as R-apomor-
and animal studies suggest that pramipexole may
phine against these agents, emphasising the rele-
protect dopamine neurons. These findings have pro-
vance of antioxidant properties in neuroprotection.
vided the rationale for assessing the progression of
R- and S-apomorphine were found to be more potent
dopamine neuronal degeneration in patients with
in inhibiting thiobarbituric acid reactive substance
Parkinson’s disease after treatment with either levo-
formation than dopamine by a factor of 20, while
dopa or pramipexole by means of dopamine trans-
pergolide showed no significant effect. In addition,
porter imaging using single photon emission com-
puter tomography (SPECT) with 2β-car-
both R- and S-apomorphine inhibit mice striatal
boxymethoxy-3β(4-iodophenyl)tropane (β-CIT)
MAO-A and -B activities, though at relatively high
labelled with
[123]
iodine.
[148]
This double-blind ran-
concentrations.
[40]
Thus, R-apomorphine appears to
domised clinical trial, conducted by the Parkinson
be one of the few drugs, if not the only, with a broad
Study Group, recruited 82 patients with early
neuroprotective spectrum in both cellular and in vivo
Parkinson’s disease at 17 clinical centres in the US
Parkinson’s disease models. However, in vivo S-
and Canada between November 1996 and August
apomorphine appears to be more potent by a factor
1997.
of ten than the R-enantiomer in protecting against
Sequential SPECT imaging showed a decline in
MPTP-induced dopaminergic neuron loss. Thus, a
mean [
123
I]β-CIT striatal uptake from baseline of
measure of caution should be taken when interpret-
10.3% (± SD9.8%) at 22 months, 15.3% (±
ing the results. This controversy will be elucidated,
SD12.8%) at 34 months and 20.7% (± SD14.4%) at
at least in part, with the advent of pure selective
46 months, approximately 5.2% per year, in the
levodopa-treated group. The mean percentage loss
dopamine receptor agonists.
in striatal [
123
I]β-CIT uptake from baseline was
Anti-apoptotic and neurotrophic activities have
significantly reduced in the pramipexole group com-
also been attributed to some dopamine agonists.
pared with the levodopa group: 16.0% (± SD13.3%)
Pramipexole has been reported to increase bcl-2
versus 25.5% (± SD14.1%) at 46 months. In spite of
expression in a concentration-dependent man-
the short duration of the study and the small number
ner,
[145]
and both its R(+) and S(
) stereoisomers
of patients, this study demonstrates a positive trend
inhibited mitochondrial cytochrome C release into
for pramipexole as a potential neuroprotective agent
the cytosol and caspase 3 and 9 activation, as well as
capable of modifying dopaminergic neuronal degen-
eration. These data highlight the need for larger,
reversed the calcein accumulation induced by MPP+
long-term studies to further compare imaging and
or β-amyloid peptide.
[146]
Similarly R-apomorphine
clinical endpoints of disease progression and to sup-
was found to induce the expression of anti-apoptotic
port a true neuroprotective action, aimed at halting
genes and their proteins, such as bcl-2 and bcl-xL,
or slowing down the progression of the disease.
and decrease that of bax in a concentration- and
Despite the encouraging results, the literature shows
time-dependent manner.
[147]
Moreover, it has been
that patients given pramipexole still deteriorate.
shown that pramipexole promotes outgrowth of
Thus, a deeper understanding of the spectrum of the
mesencephalic cell cultures (for review, see Bennett
different pathogenic mechanisms and determination
et al.
[128]
) and that R-apomorphine induces NGF and
of the most appropriate time to initiate therapy with
GDNF secretion in the culture medium of astro-
a neuroprotectant become of crucial importance.
cytes.
[130]
The potential anti-apoptotic and neurotro-
A similar outcome has recently been obtained
phic activities of these compounds in vivo, however,
with the ReQuip
as Early Therapy versus L-Dopa-
remain to be elucidated. PET (REAL-PET) study, with the nonergotic D
2
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
742 Mandel et al.
agonist ropinirole or levodopa, designed to compare duce glutamatergic transmission within either the
the rate of Parkinson’s disease progression using
striatum or the medial segment of the globus pal-
striatal fluorodopa uptake on PET as a marker of
lidus will reduce parkinsonian symptoms.
nigrostriatal function.
[149]
Although the uptake of
Extensive toxicological studies have demonstra-
striatal fluorodopa was slower in patients when
ted that excessive NMDA receptor-mediated gluta-
treatment was initiated with ropinirole compared
matergic neurotransmission can result in excitotoxic
with levodopa, this study did not show a clinical
death of neurons.
[157]
Accordingly, NMDA receptor
correlation with the imaging findings.
antagonists have been shown to protect neurons
2.2.4 Clinical Implications
from this process.
[158]
As summarised in sections 2.2.1–3, it seems that
Recently, extensive evidence for inflammation in
the neuroprotective properties of dopamine agonists
the parkinsonian substantia nigra has come from
originate from the capacity of the drugs to stimulate
identification of proliferation of reactive microg-
D
2
receptors and scavenge free radicals and chelate
lia
[159,160]
and increased levels of inflammatory cyto-
iron, as well as from their possible anti-apoptotic
kines, IL-1β, IL-2, IL-4, IL-6, transforming growth
and trophic activities. From a clinical perspective, it
factor (TGF)-α and -β and TNFα.
[161-165]
IL-1 can,
is fundamental that the neuroprotective potential of
in turn, stimulate the production of a variety of other
dopamine agonists, so convincingly demonstrated in
inflammatory mediators such as prostaglandins.
[166]
different in vivo and in vitro studies, may be applica-
Prostaglandins may induce the release of glutamate
ble to neurodegenerative diseases. The use of dop-
from astrocytes,
[167]
leading to the stimulation of
amine agonists in treating Parkinson’s disease has
glutamate receptors, depolarisation-dependent un-
generally been reported to delay the need for levo-
blocking of NMDA receptors by magnesium and
dopa by 2–3 years.
[120,150,151]
The ultimate resolution
entry of toxic amounts of calcium into the neurons.
will come from direct assessment, by means of PET
Prostaglandins may also indirectly elevate the ex-
or SPECT imaging techniques, of the rate of dopa-
minergic neuronal loss in patients receiving a dop-
tracellular level of glutamate by inhibiting its reup-
amine agonist compared with an appropriate control
take by astrocytes
[168,169]
(figure 4). If cytokine tox-
group of patients. Therefore, the future of neuropro-
icity is due to increased prostaglandin synthesis or
tection resides in the accessibility of these radio-
excess excitatory stimulation through NMDA chan-
imaging tests, along with biological presymptomatic
nels, then the administration of an antagonist at
markers and true neuronal-modifying protective
either of these steps should provide neuroprotection.
drugs, which would prevent the demise of dopamine
neurons.
2.3 NMDA Receptor Antagonists
There are a number of interactions between
glutamatergic and dopaminergic pathways in the
basal ganglia. The neurons upon which dopamine
provides an inhibitory input have an excitatory input
from corticostriatal glutamatergic neurons.
[152-155]
Parkinsonian rigidity is produced, in part, by activa-
tion of NMDA receptors in the anterior striatum or
after activation of non-NMDA receptors in the sub-
thalamic nucleus, internal segment of the globus
pallidus or substantia nigra pars reticulate.
[156]
Therefore, pharmacological manipulations that re-
Astrocyte
IL-1β
Neuron
NMDA
receptor
Stimulation
Ca
2+
Cell death
COX activityProstaglandin
Glutamate
Inflammation:
NFκB, c-jun
and JNK
Fig. 4. Involvement of inflammatory processes and NMDA recep-
tors in neuronal cell death. COX = cyclo-oxygenase; IL-1 = interleu-
kin-1; JNK = c-
j
un N-terminal kinase; NF-κB = nuclear factor κB.
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 743
2.3.1 Amantadine
this drug. However, well designed prospective stud-
The antiviral agent amantadine (1-aminoada-
ies are needed to demonstrate its potential in dopa-
mantane) is a synthetic tricyclic amine with
minergic neuroprotection.
antiparkinsonian effects, which were discovered in-
2.3.2 Memantine
cidentally.
[170]
Amantadine was first synthesised
The neuroprotective effect of memantine (1-
>40 years ago and was initially introduced as an
amino-3,5-dimethyladamantane), a noncompetitive
antiviral agent.
[171]
Its precise mode of action is
NMDA receptor antagonist, against hypoxic dam-
unclear, but at pharmacological doses it includes
age was first studied in cultured neurons from chick
anticholinergic effects,
[172]
the release of dopamine
embryo retina. The effect of memantine was similar
and blockade of dopamine reuptake into presynaptic
to but less pronounced than that of the NMDA
nerve endings.
[173]
Changes in postsynaptic receptor
antagonist dizocilpine (MK-801) in this model.
[192]
function and NMDA receptor antagonism have also
Memantine showed a long-lasting and concentra-
been suggested to be relevant at clinical doses.
[174]
tion-dependent protective effect against the ex-
Amantadine prevented retinal ganglion cell death at
citotoxic damage to cultured rat cortical neurons
high concentrations.
[175]
Similarly, amantadine pro-
induced by glutamate and NMDA, but not against
tected cultured rat cortical neurons against NMDA-
that induced by kainate or quisqualate.
[193,194]
induced toxicity.
[176]
In vivo, memantine protected against neuronal
In the MPTP animal model of Parkinson’s dis-
damage in the hippocampal CA1 subfield in a dose-
ease, amantadine had a partially protective ef-
dependent manner. Also, administration of meman-
fect,
[177]
suggesting that aminoadamantanes may not
tine immediately after ischaemia protected neurons
only ameliorate the motor manifestations of reduced
against ischaemic damage.
[192]
Additionally, it ame-
nigrostriatal transmission but also attenuate disease
liorated hypoxic ischaemic brain damage following
progression. Clearly, further studies to clarify this
bilateral carotid occlusion and hypoxia.
[175]
Similar-
question are required.
ly, a clinically relevant dose of memantine markedly
Clinical observations have suggested several
increased BDNF mRNA levels in rat limbic cortex;
beneficial effects of amantadine in Parkinson’s dis-
this effect was more widespread and pronounced at
ease, including a decrease of levodopa-induced
higher doses, which correlated with changes in
motor complications as well as neuroprotection. In a
BDNF protein levels.
[195]
This suggests that the
controlled study of amantadine, about two-thirds of
neuroprotective properties of memantine could be
the patients showed an improvement in akinesia,
mediated by the increase of endogenous production
rigidity and tremor.
[178]
These benefits were con-
of BDNF in the brain.
firmed in a placebo-controlled study, irrespective of
its administration as monotherapy or a levodopa 2.3.3 Riluzole
adjunct.
[179-183]
Recent evidence from placebo-con-
Riluzole (2-amino-6-trifluoromethoxy benzoth-
trolled studies showed beneficial effects of amanta-
iazole) is a sodium channel antagonist with antiglu-
dine on motor response complications, such as the
tamatergic properties. In vitro, riluzole was shown
wearing-off phenomena of levodopa
[184-186]
and dys-
to dose dependently reduce the loss of primary rat
kinesia.
[187,188]
mesencephalic cultures and human dopaminergic
The response to amantadine is modest in compar- neuroblastoma SH-SY5Y cells
[196]
caused by expo-
ison with levodopa. Nevertheless, amantadine pro- sure to MPP+. Riluzole (1–10 µmol/L) also attenu-
duced continued benefit after 12 years of treat- ated oxidative injury in both cell types induced by
ment
[189]
and is used frequently, at least in Europe, exposure to levodopa and 6-OHDA and reduced
for the treatment of akinetic crisis.
[190]
A retrospec- lipid peroxidation induced by Fe
3+
and levodopa in
tive clinical study by Uitti
[191]
demonstrated that primary mesencephalic cultures.
[196]
In vivo, riluzole
long-term amantadine treatment improved patient was shown to protect dopaminergic cells against
survival, suggesting a neuroprotective potential of MPTP-induced cell death in mice in a dose-depen-
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
744 Mandel et al.
dent manner, as indicated by dopamine end metabo- monkeys treated with these neurotoxins.
[207-210]
lite levels and TH and microtubule-associated pro-
Moreover, pretreatment with iron chelators such as
tein 2 (MAP2) staining in the substantia nigra;
[197]
it
deferoxamine,
[33,34,211]
apomorphine
[39,40]
and (
)-
was also shown to preserve motor functions and
epigallocatechin-3-gallate (EGCG)
[212]
in these ani-
neurological performance.
[198]
Clinical trials with
mals prevented the neurotoxic actions of MPTP and
riluzole have been stopped in light of a double-blind,
6-OHDA.
placebo-controlled and longitudinal study of pa-
Recent studies in mice in which the iron regulato-
tients at early stages of Parkinson’s disease, where
ry protein-2 (IRP2) has been knocked out have
no significant symptomatic effect on UPDRS score
revealed an accumulation of iron in the striatum,
was achieved.
[199]
with substantial bradykinesia and tremor.
[213]
Thus,
To date, no specific NMDA receptor antagonists
iron chelation may be one other approach to neuro-
without adverse effects exist and, therefore, the cur-
protection similar to the use of penicillamine (D-
rently available drugs are unsuitable for long-term
penicillamine) for the treatment of Wilson’s disease,
treatment.
in which iron and copper accumulate in neurons.
[214]
This hypothesis is strengthened by recent exciting
2.4 Iron Chelators
publications that outlined that abnormalities of brain
ferritin and iron metabolism have been linked to
One of the major pathologies of Parkinson’s dis-
gene deletions.
[215,216]
ease and other progressive neurodegenerative dis-
Although these data suggest a therapeutic poten-
eases is the accumulation of iron at those sites where
tial of iron-chelating substances, no clearcut clinical
the neurons degenerate.
[121]
Numerous studies have
evidence for a beneficial effect in neurodegenerative
shown that there is a progressive accumulation of
diseases has been provided. So far, one study has
iron in the substantia nigra of patients with Parkin-
demonstrated that deferoxamine was able to de-
son’s disease,
[17,200-202]
specifically in the substantia
crease brain iron, as assessed by magnetic resonance
nigra pars compacta but not the reticulate, even
imaging, to prevent progression of the neurological
though the latter region normally has a higher iron
symptoms and reduce plasma lipid peroxidation
[217]
content.
[160]
At the subcellular level, iron accumula-
in aceruloplasminaemia, a disorder associated with
tion has been observed in the reactive microglia,
progressive extrapyramidal symptoms and neurode-
astrocytes and oligodendrocytes and within the me-
generation of the retina and basal ganglia.
lanised dopamine neurons of the substantia nigra
pars compacta of patients with Parkinson’s disease.
In considering the initiation of clinical trials of
Furthermore, iron has been observed in the rim of
iron chelators in humans, the emphasis should be
Lewy bodies where α-synuclein, ubiquitin and TH
directed towards the development of novel, centrally
are also present.
[160]
acting, nontoxic iron chelators. Unfortunately,
deferoxamine does not cross the blood-brain barrier
Protein aggregation is now being considered one
(BBB). However, in Parkinson’s disease, the BBB
important pathway for degeneration of neurons. α-
might be selectively opened at the site of the sub-
Synuclein associated with presynaptic membranes is
stantia nigra pars reticula. In this situation it may
not toxic. However, a number of recent stud-
give rise to a selective elevation of substances that
ies
[203-206]
have shown that it forms toxic aggregates
normally do not cross the BBB, such as iron. There
in the presence of iron, and this is considered to
also exists a possibility of iron transport from other
contribute to the formation of Lewy bodies via oxi-
brain sites by axonal flow. R-apomorphine and
dative stress. The implication of the pivotal role for
EGCG have recently been shown to possess iron-
iron in dopaminergic neuron degeneration has been
chelating properties
[125,218]
and do penetrate the
strengthened by the observations that both MPTP
brain;
[219]
therefore, they should be considered for
and 6-OHDA significantly increased iron in the
clinical use.
substantia nigra pars compacta of mice, rats and
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 745
2.5 Dietary Antioxidants degenerative diseases where oxidative stress has
been implicated.
Recent reports have revealed that polyphenol
2.5.1 Tocopherol (Vitamin E)
flavonoids may be neuroprotective in neuronal pri-
The most important endogenous free radical
mary cell cultures. The flavonol epicatechin was
scavengers are tocopherol (α-tocopherol; vitamin E)
shown to attenuate neurotoxicity induced by oxi-
and ascorbic acid (vitamin C).
[220]
Their major role
dised low-density lipoprotein in mouse-derived
is to protect the sensitive polyunsaturated fatty acids
striatal neurons.
[227]
Ginkgo biloba extract, known to
in phospholipids of biological membranes. In the
be enriched with flavonoids, has been proven to be
presence of reactive oxygen species, tocopherol
one of the best radical scavengers in vitro and in
forms a stable radical that can be recycled by
vivo
[228]
and to protect hippocampal neurons from
ascorbic acid and glutathione.
[221-223]
nitric oxide or β-amyloid-derived, peptide-induced
Tocopherol was shown to exert potent antioxi-
neurotoxicity.
[229,230]
Also, the consumption of fla-
dant activity and protect mouse clonal hippocampal
vonoid-rich blueberries or strawberries reversed the
and rat cerebellar granule neurons against the oxida-
age-related cognitive and motor behavioural deficits
tive cell death induced by β-amyloid protein, hydro-
in rats.
[231]
Recently, clinical trials in patients with
gen peroxide and glutamate.
[224]
It was the first
Alzheimer’s have demonstrated potential benefits
natural antioxidant to be studied as a neuroprotec-
from treatment with the antioxidant extract of gink-
tive agent. In 1987, a 10-year clinical trial,
go biloba (for review see Pratico and Delanty
[232]
DATATOP, was initiated for the evaluation of disa-
and Clostre
[233]
).
bilities and signs of idiopathic parkinsonism in pa-
Further studies are necessary to confirm these
tients receiving placebo, tocopherol, selegiline or a
findings and explore the outcome of a cocktail of
combination of the two drugs.
[86]
Unfortunately, de-
agents with antioxidant properties in Parkinson’s
spite the potent antioxidant effect of tocopherol in
disease.
vitro, the clinical data did not provide support for it
in the treatment of Parkinson’s disease. This may be
related to either the low dose used or the duration of
Tea Extracts and Individual
Polyphenol Components
treatment that was employed. It is possible that with
larger doses and a longer treatment period, a positive
Tea is one of the most widely consumed bever-
outcome would have been obtained. In Alzheimer’s
ages in the world today, second only to water. The
disease studies,
[225]
the outcome with tocopherol
polyphenols found in tea are more commonly
was more positive, probably because the dosage was
known as flavonols or catechins and comprise
about three to four times higher than that used in the
30–40% of the extractable solid of dried green tea
DATATOP trial.
[86]
leaves.
[234]
Tea extracts and tea polyphenols have
been reported to possess anticancer and anti-in-
2.5.2 Flavonoids and Polyphenols
flammatory effects.
[234-237]
In addition, they exhibit
Flavonoids are a family of polyphenols found in antioxidant
[238-240]
and iron-chelating proper-
fruits and vegetables as well as plant beverages such ties.
[241,242]
Levites et al.
[243]
have recently reported
as tea, pomegranate juice and red wine. Because neuroprotective effects of both green and black tea
flavonoids are natural antioxidants, causing an ele- extracts against the parkinsonism-inducing toxin
vation of the antioxidant capacity of plasma after 6-OHDA, where 3 µmol/L total polyphenols
ingestion, and because of their reported ability to doubled and tripled the viability of the cells, respec-
inhibit low-density lipoprotein oxidation in vi- tively (figure 5 [a]). Similarly, the green tea individ-
tro,
[226]
they have attracted public interest as poten- ual polyphenol, EGCG (0.5–5 µmol/L), conferred
tial drugs for the treatment of cardiovascular and significant protection against the toxin
[244]
(figure 5
liver diseases, cancer, ischaemia, AIDS and neuro- [b]).
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
746 Mandel et al.
GT + 6-OHDA
BT + 6-OHDA
EGCG + 6-OHDA
0
10
20
30
40
50
0
*
0.06
**
**
0.6
**
**
3.0
**
6.0 30 60
Tea extracts (total polyphenols, µmol/L)
Cell viability (% of control)
0
20
40
60
80
100
0 10
EGCG (µmol/L)
ab
1
**
0.10.05 0.5
*
5
*
Fig. 5. Protection by tea extracts and (
)-epigallocatechin-3-gallate (EGCG) against neurotoxicity induced by 6-hydroxydopamine (6-OHDA)
in NB SH-SY5Y cells. NB SH-SY5Y cells were pretreated with increasing levels of (a) green tea (GT) or black tea (BT) extracts or (b) EGCG
15 minutes before the addition of 6-OHDA (50 µmol/L) for 24 hours. The results are the mean + standard error of the mean (n = 8) [(a)
reproduced from Levites et al.,
[243]
with permission from Elsevier Science
]
. One-wa
y
ANOVA: * p < 0.05, ** p < 0.001 vs 6-OHDA.
The protective effect of tea polyphenols has also the involvement of ERK1/ERK2 and protein kinase
C activation and regulation of cell survival/cell
been described in vivo, in a mice model of cerebral
cycle genes.
[244]
ischaemia, where intravenous injection of tea cat-
In spite of the absence of clinical trials regarding
echins
[245]
or intraperitoneal injection of EGCG
[246]
tea polyphenos and Parkinson’s disease, a recent
immediately after ischaemia reduced memory im-
epidemiological study has shown a reduced risk of
pairment and hippocampal neuronal damage, re-
Parkinson’s disease associated with consumption of
spectively. Recently, Levites et al.
[212]
reported that
two or more cups of tea per day and two or more
green tea extract (0.5 and 1 mg/kg) or its isolated
cola drinks per day.
[248]
polyphenol EGCG (2 and 10 mg/kg) prevented
MPTP-induced striatal dopamine (figure 6) and TH
2.6 NSAIDs: Cyclo-Oxygenase Inhibitors
depletion and neuronal loss in the substantia nigra of
mice.
Postmortem analysis of brain tissue obtained
One possible mechanism underlying the effec-
from patients with Parkinson’s disease has revealed
tiveness of both green and black tea extracts and
that the lesions are characterised by the presence of
EGCG may involve the catechol-like structure of the
inflammatory molecules, such as cytokines and
components, since it is known that catechol-contain-
components of complement. It is postulated that
ing polyphenols are potent radical scavengers and
inflammatory events, including proliferation of re-
chelators of ferric ions.
[247]
Similarly, dopamine and
active microglia, are substantially involved in the
the dopamine agonist R-apomorphine, both reported
pathogenesis of Parkinson’s disease.
[249]
This is also
to induce neuroprotection (see section 2.2), also
supported by activation of the stress and inflamma-
possess a catechol structure. Thus, it appears that
tory cjun N-terminal kinase (JNK) in experimental
various antioxidants with protective effects may
models of Parkinson’s disease.
[250-252]
These facts
have structure similarities.
[147]
In addition, tea have led to the prediction that anti-inflammatory
agents might be effective in treating the disease.
[253]
polyphenols may also act by regulation of cell sig-
nalling mediators. A recent study aimed at investi-
The cyclo-oxygenase (COX) enzyme catalyses
gating the molecular pathways involved in the
the first step in the conversion of arachidonic acid to
neuroprotective action of EGCG has demonstrated
prostanoids (prostaglandins and thromboxanes). It is
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 747
now clear that this enzyme exists in at least two COX-1/COX-2, may account, in part, for its
neuroprotective effect against MPTP toxicity.
distinct isoforms: a largely constitutive form termed
COX-1 and a largely inducible form termed COX-2.
However, in our hands, aspirin over a wide con-
The inducible form is expressed primarily in patho-
centration range did not prevent MPTP-induced
physiological conditions and upregulated by cyto-
striatal dopamine depletion (unpublished data). Fur-
kines and growth factors. Induction of this enzyme
thermore, other COX-1/COX-2 inhibitors such as
can lead to increased production of mediators that
paracetamol (acetaminophen), diclofenac, indo-
augment inflammatory conditions (figure 4). Differ-
methacin and ibuprofen have been reported to be
ent pathways lead to the activation of COX-2. TNFα
ineffective against MPTP toxicity.
[257]
However, in
activates COX-2 via the JNK pathway
[254,255]
and
this study, no immunostaining for TH-positive neu-
induction of nuclear factor κB (NF-κB).
[256]
There-
rons was conducted, and the conclusion was sup-
fore, the inhibition of COX-2 seems to be a good
ported only by the striatal dopamine content. Similar
mechanism for neuroprotection.
negative results were obtained by our group with the
COX-2 inhibitor nimesulide and the TNFα receptor
Aspirin (acetylsalicylic acid), the original
inhibitors thalidomide and supedimide. In cell cul-
NSAID synthesised by Hofman over a century ago,
ture experiments using mesencephalic dopaminergic
is still the most widely used medicine in the world.
neurons, aspirin or ibuprofen, both COX-1/COX-2
Aspirin, a mixed COX-1/COX-2 inhibitor, and
inhibitors, protected the cells against glutamate tox-
meloxicam, a selective COX-2 inhibitor, were found
icity.
[262]
to partially protect against MPTP-induced striatal
dopamine depletion in mice
[257-259]
and prevent the
NSAIDs represent a generous portion of the mar-
loss of TH-immunoreactive neurons in the substan-
ket of drugs used in the treatment of pain and
tia nigra pars compacta.
[258]
Inhibition of NF-κB
inflammation (see review by Jackson and Hawk-
activation
[260]
or inducible NOS,
[261]
via inhibition of ey
[263]
). There is no doubt that COX-2 inhibitors
GT (mg/kg)
Striatal dopamine (% of control)
0
20
40
60
80
100
120
140
EGCG (mg/kg)
0
20
40
60
80
100
120
140
ab
0.5
**
*
1
**
*
2
***
*
10
***
*
Control
MPTP (24 mg/kg/day)
GT
GT + MPTP
Control
MPTP (24 mg/kg/day)
EGCG
EGCG + MPTP
5
*
Fig. 6. Effect of green tea (GT) and (
)-epigallocatechin-3-gallate (EGCG) on striatal dopamine content in 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP)-treated mice. (a) C57-BL mice were injected intraperitoneally with GT (0.55 mg/kg, containing 0.33 µmoles
total polyphenols/kg) followed by a dose of MPTP (24 mg/kg, intraperitoneally) for 4 days. Respective controls received saline or GT only.
(b) C57-BL mice were administered EGCG (2 and 10 mg/kg, orally) for 10 days, and for the following 4 days the animals received a
combination of EGCG and MPTP (24 mg/kg/day, intraperitoneally). Absolute dopamine values in control, untreated mice were 74.32 ± 1.73
pmol/mg tissue (reproduced from Levites et al.,
[212]
with permission from Blackwell Publishing). * p < 0.001 vs control; ** p < 0.01, *** p <
0.05 vs MPTP alone.
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
748 Mandel et al.
have a superior peripheral gastrointestinal safety disease, suggesting a protective effect of nico-
profile compared with nonselective NSAIDs. Still,
tine.
[248,272]
However, studies on the effect of trans-
there is no long-term study on the effects of NSAIDs
dermal nicotine patches
[273]
or nicotine chewing
on the progress of neurodegeneration. Therefore,
gum
[274]
in nonsmoking patients with early-onset
additional studies are needed to support the potential
Parkinson’s disease showed no remarkable effects
of NSAIDs in the treatment of Parkinson’s disease.
on cardinal parkinsonian symptoms or auditory
event-related potentials, while in smokers the
2.7 Neuronal Nicotinic Acetylcholine
UPDRS scores improved by >10% when they were
Receptor Agonists
given these nicotine preparations.
[274]
These studies
have been reviewed by Morens and colleagues,
[275]
CNS nicotinic acetylcholine receptors are a fami-
who concluded that the association is not artifactual,
ly of ligand-gated cation channels with a generally
pentameric structure, comprising two α and three β
based on several findings: (i) >35 prospective and
subunits.
[264,265]
CNS nicotinic receptors are struc-
case-control studies have found this association in
turally and functionally different from nicotinic re-
varying study locations; (ii) dose-response effects
ceptors at the neuromuscular junction. The major
exist in a number of studies; (iii) relative protection
distinction is the high affinity of muscle receptors
appears to be afforded even in patients who have
for the snake venom toxin α-bungarotoxin. The
stopped smoking; (iv) the association cannot be
majority of nicotinic receptors in the CNS do not
explained by confounding variables or study biases;
share this effect.
and (v) there is a similar association between smok-
The precise role of CNS nicotinic receptors re-
ing history and a reduced incidence of Alzheimer’s
mains unclear. In vitro studies
[266,267]
have suggested
disease. Although epidemiological studies do not
that nicotinic receptor activation leads to the release
confirm that it is the nicotine in tobacco that is the
of acetylcholine, dopamine and other monoamines.
protective agent, it remains the best candidate con-
More recently, in vivo studies using microdialysis
stituent.
techniques
[268]
have verified that nicotinic stimula-
Addiction to nicotine has been linked to high
tion leads to acetylcholine release under physiologi-
levels of cerebral dopamine.
[276]
Moreover, since
cal conditions.
nicotine is associated with the release of striatal
In contrast to many other receptors, there have
dopamine, smoking may postpone the development
been consistent reports of substantial changes in
of clinical symptoms in Parkinson’s disease by vir-
nicotinic receptors with aging (postmaturity) and
tue of elevating synaptic dopamine levels. Several
disease. These changes invariably consist of a re-
neuroprotective actions of smoking in Parkinson’s
duction in the number, but not the affinity, of the
receptors. Changes in CNS cholinergic systems
disease have been suggested: (i) activation of the
have been shown to occur in the brains of patients
nicotine calcium channels;
[277]
(ii) increased mela-
with Parkinson’s disease. In particular, a similar loss
nin in smokers, which may act as a neurotoxic
of cholinergic cells in the basal forebrain nuclei to
‘sink’
[278]
by binding cell toxic factors and removing
that which occurs in Alzheimer’s disease has been
them from the cytosol; (iii) induction of cytochrome
described in Parkinson’s disease.
[269]
The loss of
P450, induced by aromatic hydrocarbons in tobacco
cholinergic markers in the cortex
[270]
that may occur
smoke, which may promote detoxification of toxic
in Parkinson’s disease could be related to lesions in
agents implicated in the development of the dis-
these nuclei and other cholinergic projections to the
ease;
[279]
(iv) presence of hydrazine in the smoke,
cortex.
[271]
suggested to protect dopaminergic nigrostriatal neu-
rons from MPTP-type damage;
[280]
and (v) regula-
2.7.1 Smoking and Parkinson’s Disease
tion of neurotrophic factor genes by nicotine acetyl-
A number of studies have shown that smokers
choline receptor signalling.
have a lower than expected incidence of Parkinson’s
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 749
Cell culture studies employing ventral mesence- sonian patients. The authors reported significant im-
phalic neurons have shown that pretreatment with provement in the symptoms after 1 year and an
nicotine protected against MPP+-induced cell increase in putamen dopamine storage after 18
death.
[281,282]
In rat brain mitochondrial preparations, months. Based on both laboratory and clinical data,
nicotine was able to inhibit lipid peroxidation in- GDNF therapy seems a promising approach for
duced by 6-OHDA autoxidation.
[283]
In animals, nic- Parkinson’s disease.
otine promoted dopamine release and protected
3. Future Strategies for Neuroprotection
against the degenerative changes associated with
unilateral lesioning of nigrostriatal pathways
[284,285]
Although we have discussed the neuroprotective
and against MPTP
[286]
and 6-OHDA
[287]
toxicity.
strategies of several drugs in the previous sections,
Recently, an increasing number of potent nicotin-
almost all the drugs mentioned above have not been
ic acetylcholine receptor agonists have been found
demonstrated as having neuroprotective effects in
displaying selective affinities for nicotinic recep-
Parkinson’s disease. Thus, they can also be included
tors, some of which are considered potential candi-
in the category of future neuroprotective strategies.
date targets for the treatment of neurodegenerative
The following section discusses novel proposed tar-
diseases such as Parkinson’s and Alzheimer’s dis-
gets for drug intervention that have emerged from
ease.
[288,289]
very recent studies in the field.
Despite the number of studies on the contribution
of smoking to lowering the risk of Parkinson’s dis-
3.1 Anti-Apoptotic Drugs: Mitochondria,
ease, more systematic reviews and epidemiological
Calcium Channels and Caspases as
and large-scale clinical studies are warranted to con-
Potential Targets
firm a possible therapeutic value of nicotine in
Accumulating evidence strongly suggests a cen-
Parkinson’s disease.
tral role for defective mitochondrial energy produc-
tion in Parkinson’s disease. The majority of patients
2.8 Neurotrophic Factors
with mitochondrial disease have neuronal loss,
GDNF is the most studied neurotrophic agent in
gliosis and degeneration. Drug strategies directed to
animal models of Parkinson’s disease. GDNF deliv-
correct mitochondrial defects may include rasagiline
ered via a lentiviral vector has been shown to reverse
(see section 2.1.2) and bioenergetic drugs such as
functional deficits and completely prevent nigrostri-
ubidecarenone (coenzyme Q10), creatine and gink-
atal neurodegeneration in primate models of Parkin-
go biloba, shown to produce significant neuropro-
son’s disease.
[290]
More recently, GDNF was found
tective effects in the MPTP model of Parkinson’s
to mediate cell plasticity, as demonstrated by the
disease.
[294]
Oncoproteins (bcl-2 and bcl-xL) may
fact that it induced an increase in TH-responsive
also have indirect anti-apoptotic properties, as re-
striatal cells in aged and parkinsonian nonhuman
cently reviewed by Linazasoro.
[15]
primates.
[291]
Putative therapeutic targets include the permea-
In spite of these encouraging results, a clinical bility transition pore of the mitochondrial membrane
trial conducted with one patient who had Parkin- and the release of cytochrome C and other pro-
son’s disease showed no beneficial outcome after apoptotic proteins from mitochondria. Cyclosporin
monthly intracerebroventricular injections of A, which blocks the mitochondria voltage depen-
GDNF, and the patient experienced severe adverse dent anion channel (VDAC), has been shown to
effects.
[292]
The application of protein to the target possess neuroprotective action against MPTP.
[295]
site may account for the therapeutic failure and, More recently, the mechanism of anti-apoptotic ac-
therefore, alternative delivery methods should be tion of rasagiline has been attributed to prevention
explored. In a recent phase I clinical trial,
[293]
GDNF of the opening of VDAC, release of cytochrome C
was directly delivered to the putamen of five parkin- and activation of caspase 3.
[296]
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
750 Mandel et al.
Calcium channels also may be considered poten- tors.
[305,306]
Two receptor subtypes (CB
1
and CB
2
)
tial therapeutic targets in Parkinson’s disease, with
that are only partially homologous were identi-
the aim being to modulate the opening of both
fied.
[305]
While CB
1
receptors were found to be
cellular and mitochondrial channels. A previous
present in the CNS,
[307]
CB
2
receptors were found in
study has shown promotion of grafted dopaminergic
macrophages and the marginal zone of the
neuron survival by the calcium channel antagonist
spleen.
[305]
Cannabinoids can thus modulate the ac-
flunarizine.
[297]
However, a high prevalence of
tivity of both the CNS and immune systems. Addi-
flunarizine- and cinnarizine-induced parkinsonism
tionally, the identification of two endogenous
in humans has been reported, probably occurring as
ligands for the cannabinoid receptors 2-arachido-
a result of a reduction in presynaptic dopamine
noylglycerol (2-AG) and anandamide,
[308-310]
named
levels via interference with the storage of dopamine
‘endocannabinoids’, has opened the way to under-
in synaptic vesicles.
[298]
Calcium channel antagon-
standing the role of the cannabinoid system. These
ists also possess other biological effects via calcium-
molecules were suggested to have a neuromodulato-
independent mechanisms and, therefore, more spe-
ry action (see review by Di Marzo et al.
[311]
). The
cific antagonists are required with negligible effects
high levels of CB
1
receptors within the basal gan-
on catecholamine metabolism.
glia
[312]
suggest a potential role for endocannabi-
Studies from human postmortem brains suggest
noids in the control of voluntary movements and in
that caspases are activated in parkinsonian pa-
basal ganglia-related movement disorders such as
tients.
[299]
Caspase inhibitor-directed strategies have
Parkinson’s disease.
[313-315]
been suggested to reduce both acute and chronic
Cannabinoids such as tetrahydrocannabinol and
neurodegenerative conditions.
[300]
Despite in vitro
other agonists were found to suppress nitric oxide
and in vivo studies indicating that caspase inhibition
release from macrophages by mechanisms involving
promotes neuronal survival and functional outcome,
cannabinoid receptors.
[316]
Additionally, it was re-
caspase targeting alone may be insufficient to re-
verse the effects of various death stimuli, as pre-
ported that tetrahydrocannabinol and its psycho-
viously suggested by some authors.
[301,302]
active analogues are neuroprotective against gluta-
One major problem concerning the use of anti-
mate toxicity in vitro by activating cannabinoid re-
apoptotic drugs is the BBB penetration and tissue
ceptors,
[317,318]
with resulting presynaptic inhibition
selectively, not only to assure a proper concentration
of glutamate release.
[319]
Cannabidiol, a nonp-
but also to avoid interference with the physiological
sychoactive cannabinoid, and other cannabinoids
programmed cell death machinery. Thus, at least at
such as tetrahydrocannabinol were reported to be
this stage, the potential benefits of these agents
potent antioxidants that protect neurons from gluta-
should be weighed against their possible pro-neo-
mate-induced death, even without cannabinoid re-
plastic, proliferative actions.
ceptor activation.
[320]
Their properties were exam-
ined in the Fenton reaction, and it was observed that
3.2 Cannabinoids
cannabinoids can act as potent reducing agents.
[320]
Giuffrida and colleagues
[321]
have shown the exis-
Marijuana (Cannabis sativa) was one of the first
tence of an inhibitory loop by which endocannabi-
plants used by humans to treat a wide range of
noids modulate dopaminergic control of voluntary
medical conditions.
[303]
In the late 19th century,
movement, and this may have important implica-
marijuana was often prescribed for parkinsonian
tions for the development of therapies for movement
tremor, apparently with benefit. With time, after the
disorders.
discovery of other beneficial drugs, the medicinal
In parkinsonian rats, the CB
1
antagonist rimona-
use of marijuana has become controversial.
[304]
bant (SR141716A) was found to restore full motor
Renewed interest in the effects of cannabinoids
started with the discovery of cannabinoid recep- activity.
[311]
On the other hand, in primates, the same
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 751
cannabinoid antagonist was ineffective in alleviat- There are serious health risks associated with
ing parkinsonian symptoms.
[322]
taking MDMA.
[331,332]
Its use is rarely fatal, but it
can cause memory blackouts and depression and
The proposed ability of cannabinoids to be
may be especially damaging to people with Parkin-
neuroprotective in Parkinson’s disease has not yet
son’s disease. The challenge for scientists is to find a
been studied in humans. The single study to date,
drug that will replicate the effect of MDMA with
which aimed to investigate the possible benefit from
none of the attendant dangers.
cannabinoids in patients with Parkinson’s dis-
ease
[323]
other than reduction of levodopa-induced
3.4 Nitric Oxide Synthase Inhibitors
dyskinesia, does not support the notion that marijua-
na (when smoked) reduces tremor or other parkin-
NOS inhibitors represent another possible ap-
sonian disabilities. This study addressed the acute
proach to neuroprotection, given that nitric oxide
effects on parkinsonian symptoms. Therefore, it is
has been shown to be involved in the pathological
still not clear whether long-term treatment with can-
processes in Alzheimer’s and Parkinson’s dis-
nabinoids may provide neuroprotection.
ease.
[43,44]
Both in vitro and animal models of
Parkinson’s disease have shown protection with
3.3 Ecstasy
several nonselective and selective inhibitors for the
different NOS isoforms.
[333]
Selective NOS inhibi-
Methylenedioxymethamphetamine (MDMA, Ec-
tors may provide a novel therapeutic approach to
stasy) is a drug of abuse that affects the monoamin-
neuroprotection and to investigate other biological
ergic systems of rodents and nonhuman primates. In
functions of nitric oxide.
rats, MDMA causes marked and persistent depletion
of serotonin, which is associated with serotonergic
3.5 Multidrug (Cocktail)
terminal cell loss.
[324,325]
In contrast, MDMA injec-
Neuroprotective Therapy
tions given to mice cause striatal dopamine deple-
tion without significantly affecting the serotonergic
It is now apparent that neurodegeneration in
system.
[326-328]
In addition, it was shown that a single
Parkinson’s disease or other neurodegenerative dis-
administration of MDMA causes an increase in
eases constitutes a complex set of reactions leading
striatal dopamine release in rats.
[329]
to the death of neurons. This is significantly illus-
Recently, a documentary film was shown on the
trated in our recent study employing cDNA microar-
BBC programme Horizon about MDMA and
ray in the mice MPTP model of Parkinson’s disease
Parkinson’s disease.
[330]
The documentary was
(see section 1.2.1) and more recently by others in
about a film stuntman, who at 34 years of age was
ischaemia and Alzheimer’s disease models,
[334,335]
diagnosed with the disease; his symptoms did not
where the expression of thousands of genes can be
respond to levodopa treatment, and he developed
measured at once. These studies have shown that
bradykinesia. He discovered that MDMA was much
there is a cascade of ‘domino effects’ that results in
more useful than conventional therapy. The trans-
elevation in the expression of genes related to oxida-
formation of the patient on the video is astonishing,
tive stress, inflammation, nitric oxide, cell cycle,
but brain scans at Hammersmith Hospital, London,
iron metabolism, glutamate excitotoxicity and neu-
UK, revealed no changes in the dopamine levels in
rotrophic factor pathways, as well as in cell cycle
his brain.
regulators and signal transduction molecules (figure
Meanwhile, in Manchester, UK, a pair of scien- 2).
[49]
Thus, dopaminergic neurodegeneration in idi-
tists has been studying ways of treating Parkinson’s opathic Parkinson’s disease as well as in parkinson-
disease that do not involve dopamine. Their theory ism induced by neurotoxins appears to incite a com-
suggests that serotonin may be involved. The prima- plex set of events, which a single neuroprotective
ry action of MDMA in the brain is to release large drug may not be able to stop. Indeed, this may be
amounts of serotonin from nerve endings. one reason why the limited number of clinical
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
752 Mandel et al.
neuroprotective therapies have, so far, failed to commonly used treatment is dopamine replacement
show significant results. Another possibility may be
therapy with levodopa or dopamine receptor ago-
that the animal models used for Parkinson’s disease
nists or increasing the availability of brain dopamine
are not truly representative of the pathology of the
with inhibitors of enzymes that metabolise dop-
disease.
amine (MAO-A and -B and catechol-O-methyl-
transferase).
Future neuroprotective strategies in Parkinson’s
(and Alzheimer’s) disease should include an ap-
If neuroprotective therapy is to be realised in
proach similar to the multidrug therapy employed in
Parkinson’s disease, major consideration should be
the treatment of AIDS and cardiovascular diseases.
given to the optimal time at which to initiate the
Although this may be complex, continuing the em-
neuroprotective attempts. It seems plausible that
ployment of single neuroprotective drugs is unlikely
efforts must be aimed at the preclinical stage of the
to be sufficient, given that they have all failed in the
disease, when damage is not yet sufficient for symp-
clinic. Indeed, recent animal studies are confirming
toms to be noticeable. However, our ability to iden-
this hypothesis, demonstrating that a dose of a single
tify this preclinical state is currently very limited,
neuroprotective drug that, per se, does not induce
and the few studies so far completed have not come
neuroprotection in an ischaemia model, acts in a
to a clearcut conclusion. A much better understand-
synergistic fashion when combined with a subther-
ing of the biochemical pathology and the relation-
apeutic dose of another neuroprotective drug.
[336]
ship between gene mutations, protein misfolding,
cDNA microarray gene expression analysis of
accumulation of aggregated α-synuclein and
dopaminergic neurodegenerative process is not a
proteasome impairment may contribute to a better
simple mechanism. It has clearly demonstrated that
understanding of the disease, as well as to the devel-
the ‘domino’ cascade of events described above can
opment of novel drugs.
be initiated by any of the neurotoxic events at any
Despite two recent trials of pramipexole and
point in the cascade. This may lead to the extensive-
rasagiline that have shown a positive trend, the
ly discussed issue concerning the definition of
general failure to induce neuroprotection in the clin-
Parkinson’s disease: is it a syndrome or a disease?
ic versus in the laboratory with currently available
The complexity of neurodegeneration, as shown by
drugs suggests that a single drug would not be
cDNA gene array studies, suggests that Parkinson’s
sufficiently active and/or that the animal models we
disease may represent a syndrome, because the dis-
are employing are not truly representative of the
ease could be initiated by alterations in any of the
disease state. Consequently, a number of investiga-
biochemical events in the cascade. Thus, it seems
tors have started to look at combination treatment in
likely that the action of the various putative
neurodegenerative disorders, an approach increas-
neuroprotective drugs so far described would affect
ingly used in the management of other diseases such
only one or two biochemical reactions in the ‘domi-
as AIDS, ischaemia and neurotrauma. These at-
no effect’ described for MPTP-,
[49]
6-OHDA-
[53]
and
tempts have been accompanied, in many cases, with
methamphetamine-induced neurotoxicity.
[50,51]
parallel brain imaging studies, such as PET and
SPECT, to assess disease progression in patients
4. Conclusion
repeatedly throughout the course of their illness.
The mass of information from the human genome
The ultimate aim of therapy for Parkinson’s dis-
project offers diverse potential molecular targets for
ease must be to identify the disease process long
specific drug intervention in disease. Systematic use
before symptoms arise, such that therapy can be
of pharmacogenetics to detect the affected gene(s) in
given early enough to forestall the neuronal destruc-
a particular patient so as to adapt the best therapy
tion that underlies patients’ discomfort and disabili-
according to his/her requisites, together with the use
ty. The current therapeutic approach to the treatment
of biological markers and the development of new
of Parkinson’s disease is still symptomatic; the most
Adis Data Information BV 2003. All rights reserved. CNS Drugs 2003; 17 (10)
Update on Neuroprotective Strategies in Parkinsons Disease 753
16. McNaught KS, Belizaire R, Jenner P, et al. Selective loss of 20S
drugs aimed to slow down or prevent the progres-
proteasome alpha-subunits in the substantia nigra pars com-
sion of Parkinson’s disease, represents the future
pacta in Parkinson’s disease. Neurosci Lett 2002; 326 (3):
155-8
approach to neuroprotection.
17. Riederer P, Sofic E, Rausch WD, et al. Transition metals,
ferritin, glutathione, and ascorbic acid in parkinsonian brains. J
Acknowledgements
Neurochem 1989; 52 (2): 515-20
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iron in the etiopathology of Parkinson’s disease. Mov Disord
The authors acknowledge the support of Teva Pharmaceu-
1993; 8 (1): 1-12
ticals Ltd (Israel), the National Parkinson Foundation (USA)
19. Gotz ME, Kunig G, Riederer P, et al. Oxidative stress: free
and the Stein Foundation (PA, USA) in the preparation of this
radical production in neural degeneration. Pharmacol Ther
manuscript. The contribution of Ms Iris Fichmann in editing
1994; 63 (1): 37-122
the manuscript is gratefully acknowledged. The authors have
20. Jenner P, Olanow CW. Oxidative stress and the pathogenesis of
no conflicts of interest related to the content of this manu-
Parkinson’s disease. Neurology 1996; 47 (0028-3878): 161-70
script.
21. Olanow CW, Youdim MB. Iron and neurodegeneration: pros-
pects for neuroprotection. In: Olanow CW, Jenner P, Youdim
MB, editors. Neurodegeneration and neuroprotection in
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... In particular, the brain is vulnerable to oxidative damage and apoptosis induction by abnormal calcium and ATP levels due to its high energy metabolism rate, high oxygen consumption, and high ratio of polyunsaturated fatty acids [105][106][107][108][109][110]. Oxidative stress is attracting attention as a cause of several neurodegenerative diseases [111][112][113]. The blockade of NLRP3 delays neuronal pyroptosis in LDLr −/− mice and cultured LDLr −/− neurons after experimental stroke [91]. ...
... In particular, the brain is vulnerable to oxidative damage and apoptosis induction by abnormal calcium and ATP levels due to its high energy metabolism rate, high oxygen consumption, and high ratio of polyunsaturated fatty acids [105][106][107][108][109][110]. Oxidative stress is attracting attention as a cause of several neurodegenerative diseases [111][112][113]. ...
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