Challenges
Neuroprotection by monoamine
oxidase B inhibitors:
a therapeutic strategy
for Parkinson’s disease?{
Rinat Tabakman,{ Shimon Lecht, and Philip Lazarovici*
Summary
Parkinsonism (PD) is a neurodegenerative disorder of the
brain resulting in dopamine deficiency caused by the
progressive death of dopaminergic neurons. PD is char-
acterized by a combination of rigidity, poverty of move-
ment, tremor and postural instability. Selegiline is a
selective and irreversible propargylamine type B mono-
amine oxidase (MAO-B) inhibitor. This drug, which in-
hibits dopamine metabolism, has been effectively used in
the treatment of PD. However, its therapeutic effects are
compromised by its many neurotoxic metabolites. To
circumvent this obstacle, a novel MAO-B inhibitor, rasagi-
line, was developed. Paradoxically, the neuroprotective
mechanism of propargylamines in different neuronal
models appears to be independent of MAO-B inhibition.
Department of Pharmacology, School of Pharmacy, Faculty of
Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
*Correspondence to: Philip Lazarovici, Department of Pharmacology
and Experimental Therapeutics, School of Pharmacy, Faculty of
Medicine, The Hebrew University, Jerusalem, 91120, Israel.
E-mail: lazph@md.huji.ac.il
y
This review is part of a PhD thesis to be submitted to the Hebrew
University of Jerusalem by TR.
z
The scientific views and opinions expressed in this article are solely
those of the authors and are not to be construed as having any
commercial interest.
DOI 10.1002/bies.10378
Published online in Wiley InterScience (www.interscience.wiley.com).
Abbreviations: PD, Parkinson’s disease; UPDRS, unified Parkinson’s
disease rating scale; SN, substantia nigra; DA, dopaminergic; MAO-B,
type B monoamine oxidase; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; SOD, superoxide dismutase; NADþ, nicotinamide
adenine dinucleotide; FAD, flavin adenine dinucleotide; BDNF, brain-
derived neurotrophic factor; NGF, nerve growth factor; GDNF, glial
derived neurotrophic factor; DMS, desmethylselegiline; MPPþ, 1-
methyl-4-phenyl pyridinium; MPTP, N-methyl-4-phenyl-1,2,3,6-tetra-
hydropyridine; 6-OH-DA, 6-hydroxydopamine; OGD, oxygen–glucose
deprivation; PET, positron emission tomography; fMRI, functional
magnetic resonance imaging; IC50, 50% inhibitory concentration; Ki,
inhibition constant; PC12, pheochromocytoma cells.
80 BioEssays 26.1
Recent investigations into the neuroprotective mechan-
ism of propargylamines indicate that glyceraldehyde-3-
phosphate dehydrogenase (GAPDH), MAO-B and/or
other unknown proteins may represent pivotal proteins
in the survival of the injured neurons. Delineation of the
mechanism(s) involved in the neuroprotective effects
exerted by MAO-B inhibitors may provide the key to
preventive novel therapeutic modalities. BioEssays
26:80–90, 2004. ß 2003 Wiley Periodicals, Inc.
Introduction
Parkinson’s disease (PD) is a progressive movement disorder
that affects 1–2%of the adult population over 60 years of age.
The main symptoms are tremor at rest, muscular rigidity and a
decrease in the frequency of voluntary movements (hypoki-
nesia).(1) For many years, it has been known that PD synd-
rome is due to a disorder of the basal ganglia, brain structures
regulating motor activity and innervated by one of the brain’s
major dopaminergic pathways. The neurochemical basis for
the disease was discovered in 1960 by Hornykiewics,(2) who
showed that the dopamine content of the substantia nigra (SN)
and corpus striatum in postmortem PD brains was extremely
low (less than 10% of normal). Pathologically, PD is charac-
terized by progressive degeneration of pigmented brain stem
nuclei, mostly the pars compacta of the SN, along with the
formation of characteristic eosinophilic cytoplasmic inclusions
known as Lewy bodies.(3) The disease progresses slowly for
many years. The clinical symptoms are due to the degenera-
tion (death) of dopaminergic neurons in the SN, resulting in a
dramatic decline in dopamine level. Diagnosis can be made
when at least 60% of the dopaminergic SNc neurons are lost.(4)
Many factors are considered to contribute to the pathogenesis
of PD: genetic,(5) age-related,(6) enviromental toxins,(7) and
oxidative stress.(8,9) In the past decade, novel hypotheses
have been forwarded suggesting important pathological con-
tributions to dopaminergic neuronal cell death: glutamate
neurotoxicity,(10) mitochondrial abnormalities, disturbances in
intracellular calcium homeostasis, altered iron metabolism
and apoptosis.(9,11 –14) Although the genes responsible for
a few rare familial cases have been uncovered,(15–17) the
BioEssays 26:80–90, ß 2003 Wiley Periodicals, Inc.

molecular basis for the more prevalent idiopathic PD remains
unknown. Novel technologies including DNA-microarray(18)
and single nucleotide polymorphisms(19) are expected to
pinpoint the pathogenesis of this disorder. In addition, new
techniques in neuroimaging such as positron emission tomo-
graphy (PET) and functional magnetic resonance imaging
(fMRI) may provide better means of assessing SN function.(20)
In this review, we briefly summarize the emerging knowledge
regarding the complex mechanism of action of type B mono-
amine oxidase (MAO-B) inhibitors, an important family of
drugs used to treat PD. While the search for MAO-B inhibitors
has turned up some promising propargylamine candidates,
their mode of action in ameliorating PD cannot be explained
solely by MAO-B inhibition. Today, the basis for their neuro-
protective mechanism of action is being actively pursued. We
hypothesize that the beneficial role of MAO-B inhibitors in PD
is due to a shift from neurotoxicity to neuroprotection of the
injured dopaminergic neurons.
Apoptosis and Parkinson’s disease
Since 1996, when apoptotic death was discovered in
dopaminergic cells of Parkinsonian patients,(21) many addi-
tional studies have suggested the involvement of an apoptotic
mechanism in this disorder. Apoptosis, a delayed form of cell
death associated with the activation of a ‘‘genetic program’’, is
an important biological process controlling cell number in
various tissues. This mechanism plays an important role in the
development of the nervous system(22) and is also triggered
following pathological events such as stroke and neurode-
generative diseases.(14) The SN of PD patients shows an
increase in caspase activity and in the pro-apoptotic Bax
protein, as well as nuclear translocation of glyceraldehyde-3-
phosphate dehydrogenase (GAPDH), indicating the activation
of apoptotic signals.(23–25) However, it is not clear whether the
degeneration associated with PD involves a fast ‘event’ in
which a significant number of dopaminergic neurons deterio-
rate as a result of unknown factor(s),(26) or a very slow one that
may last several decades.(27) Furthermore, other postmortem
studies, based on nick-end labeling of fragmented DNA,(28)
Bcl-2 and Bax apoptotic protein markers,(27) failed to show a
significant contribution of apoptosis to SN dopaminergic
neuronal cell death. An additional complication adding to the
cell death controversy in PD is the finding that, in postmortem
tissue, apoptotic markers are present in the glia but not in SN
neurons.(29,30) In general, nigrostriatal dopaminergic neurons
are lost with age. This phenomenon is dramatically acceler-
ated in Parkinson’s patients. The grounds for the vulnerability
of the nigrostriatal dopaminergic neurons are unknown and the
precise mechanism of cell death awaits further investigation.
The gene-expression microarray technique is expected to
make a significant contribution to the identification of gene
products involved in cell death and leading to PD.(18)
Challenges
Therapeutical approaches
to Parkinson’s disease
As the cause of the death of the dopaminergic neurons is not
known, drugs that can arrest and/or reduce and/or delay the
cell death process in dopaminergic neurons are not available.
However, significant symptomatic relief has been obtained by
the use of different dopaminergic drugs that fall into the follow-
ing categories: dopamine precursors (levodopa); compounds
mimicking (agonists) the action of dopamine (bromocriptine);
agents that prevent dopamine degradation (MAO-B inhibitors
such as rasagiline).
Levodopa, a dopamine precursor that crosses the blood–
brain barrier, is initially effective in most patients, but often
loses its efficacy after several years of treatment, the period
varying from one patient to another. Complications associated
with its use are involuntary movements, which occur in many
patients within several years, and an unpredictable ‘‘on–off’’
effect in the course of treatment.(31) Other adverse effects
include queasiness (nausea), a drop in blood pressure
(hypotension), and, occasionally, psychotic symptoms.(31)
Levodopa treatment requires a certain number of live dopami-
nergic neurons to convert this metabolic precursor into the
neurotransmitter dopamine (DA). As a result, the amount of
synaptic DA is increased and the DA deficiency characteristic
of PD is corrected. The disadvantage of this therapeutic
approach is the augmented cell death of large numbers of DA
neurons during PD progression, leading to less DA synthesis
during levodopa treatment and rendering it less effective.
Drugs that mimic DA (agonists) are less effective than
levodopa.(32) They activate postsynaptic DA receptors in the
SN and improve motor function independently of DA neuron
degeneration.
The first generation of MAO inhibitors, originally synthe-
sized in the 1950s, was used as antidepressants due to their
inhibitory effect on the metabolism of monoamine neurotrans-
mitters. These inhibitors are both irreversible and non-selec-
tive. However, their use as antidepressants was restricted
because of hepatotoxicity(33) and due to an increase in blood
pressure (hypertensive response) following the ingestion of
some foods and drinks containing tyramine,(34) which are nor-
mally metabolized in the gastrointestinal tract by MAO.(34,35)
As a result of MAO inhibition, the ingested tyramine enters the
circulation and is actively taken up by peripheral adrenergic
neurons, displacing stored noradrenaline and giving rise to a
hypertensive response that can be fatal.(36) This side-effect
pharmacological phenomenon(37) was named the ‘‘cheese
effect’’, since many cheeses are rich in tyramine. The next
discovery was made by Johnston,(38) who showed that the
MAO enzyme exists in two forms: A and B. This led to the
synthesis of a new generation of MAO inhibitors exhibiting
greater selectivity toward the individual isoforms. MAO-A
inhibitors are potent antidepressants but, since MAO-A is the
major isoform in the intestine, they induce the ‘‘cheese effect’’.
BioEssays 26.1 81
Challenges
The finding that MAO-B inhibitors have weaker antidepressant
activity, do not induce the ‘‘cheese effect,’’(39) but can amelio-
rate PD symptoms, was the basis for modern Parkinson
therapeutics,(39,40) using the MAO-B inhibitor selegiline and
rasagiline. Selegiline has been approved for use in the USA as
an adjunct to levodopa but not for monotherapy; rasagiline is a
new addition to the MAO-B inhibitor group.
Monoamine oxidases and inhibitors
in Parkinson’s disease
MAO (EC 1.4.3.4) oxidatively deaminates monoamine neuro-
transmitters (norepinephrine, epinephrine, serotonin and
dopamine), as well as exogeneous amines (e.g., tyramine).
The end products of the enzymatic reaction are aldehydes and
hydrogen peroxide, both toxic to DA neurons. The physio-
logical role of MAO is to terminate the action of several
neurotransmitters and to detoxify exogenous monoamines.
Two MAO subtypes, MAO-A and MAO-B, were defined in
1968,(38) based on their differential sensitivity to irreversible
inhibitors. 20 years later, the corresponding cDNAs of these
two subtypes were cloned. Sequence comparison indicated
72.6% amino acid homology.(41,42) The genes encoding the
two subtypes have been localized to human chromosome
Xp11.23-Xp11.4.(43) The MAO-A and MAO-B genes are homo-
logous at the level of intron–exon organization and in co-factor
FAD-binding site, and both enzymes are located at the outer
mitochondrial membrane.(44) Along with the similarities, MAO-
A and MAO-B display differences in their numbers of amino
acids, 527 and 520, and molecular weights 59.7 kDa and
58.8 kDa, respectively. The in vivo substrate affinity in humans
also differs: MAO-A metabolizes mainly serotonin, norepi-
nephrine and epinephrine, whereas MAO-B metabolizes
dopamine and phenylethylamine.(44) Both MAO-B and MAO-
A are widely distributed in the human body, the ratio between
them varying in different tissues. The highest value (>69) is
found in platelets; lower ratios were detected in the human
brain, the highest of which (5.5) was found in the SN.(45) The
selectivity toward different endogenous substrates, together
with tissue-specific localization, determines the clinical poten-
tial of each isoform. Inhibition of MAO activity in the brain
increases the synaptic level of the neurotransmitters seroto-
nin, noradrenaline and dopamine. This mechanism was
exploited to treat depression, first with nonselective MAO
inhibitors and, more recently, with selective MAO-A inhibitors.
Today however, inhibitors of MAO-A are not the drugs of first
choice in the treatment of depression, mainly because of the
development of novel antidepressants that act by different
pharmacological mechanisms, without eliciting the cheese
effect.
Many selective MAO-B inhibitors, potentially applicable to
PD treatment, have been synthesized. They are categorized
according to chemical structure, each including several
derivatives (Table 1). The most-potent and selective group
82 BioEssays 26.1
consists of propargylamine derivatives. These are irreversible
inhibitors, which would ensure continuous dopaminergic
stimulation, considered a major therapeutic goal. Lazabemide,
a 2-aminoethyl carboxamide derivative, which is a reversible,
highly selective antioxidant, was developed as a MAO-B
inhibitor for treatment of PD.(46) Clinical trials with this com-
pound were discontinued in phase III of the clinical study due
to the abnormal liver functions that developed in patients
undergoing this treatment. To date, of the variety of selective
MAO-B inhibitors investigated, only one, selegiline (l-depre-
nyl) (Table 1), has been in clinical use since the mid 1970s.(47)
Rasagiline (N-propargyl-1-R-aminoindan) (Table 1), a novel,
potent, selective, and irreversible inhibitor of MAO-B, absorb-
ed after oral administration,(48,49) is currently being evaluated
in phase III clinical trial.(40) In contrast to selegiline, rasagiline is
not metabolized to potentially toxic amphetaminic metabolites
and its major metabolite, 1-R-aminoindan, has exhibited
beneficial effects in animal models of PD.(50) Because of its
selectivity towards MAO-B, rasagiline does not trigger the
‘‘cheese effect’’,(51) and was found to improve motor and
cognitive function in PD animal models.(50) A recent clinical
trial demonstrated the beneficial influence of rasagiline mono-
therapy in early stages of Parkinson’s disease.(40) To evaluate
the safety and efficacy of rasagiline, a multicenter clinical trial
was carried out in which a total of 404 patients in early stages of
PD were included. The participants were randomly assigned to
groups receiving rasagiline at a dose of 1–2 mg per day or
corresponding placebo. A one-week escalation period was
followed by a 25-week maintenance period. The efficacy of
treatment was evaluated according to the Unified Parkinson’s
Disease Rating Scale (UPDRS); rasagiline monotherapy at
both doses proved effective.(40)
Although inhibition of MAO-B is of prime importance in
controlling PD symptoms, it appears that this inhibition under-
lies many additional effects in the brain. An interesting analogy
can be drawn between PD patients chronically administered
MAO-B inhibitors and knockout mice lacking the gene encod-
ing MAO-B. Chen et al. demonstrated significant upregulation
(
30%) of D2 receptors in the striatum and the functional
supersensitivity of D1 receptors in the mouse nucleus accum-
bens.(52) This upregulation resembles similar regulation of the
dopamine receptors observed in PD patients chronically
treated with MAO-B inhibitors. It has been suggested that
MAO-B makes a smaller contribution than MAO-A to dopamine
metabolism in the mouse, as compared with man,(53) making it
difficult to conclude that similar changes occur in MAO-B
inhibitor-treated patients. However, subjects in whom the
MAO-B gene is deleted (atypical Norrie disease) have normal
levels of DA metabolites in their plasma.(54) The parallelism
between MAO-B knockout mice and humans with a deleted
MAO-B gene, suggests a similarity in the lack of change in
DA metabolites levels This additional circumstantial evidence
leads us to postulate that upon treatment with MAO-B
 Challenges

Table 1. Classification of MAO-B inhibitors of clinical relevance, according to chemical structure, potency,
mechanism of action and selectivity
MAO-B inhibition Mechanism Selectivitya
Chemical group Chemical structure (IC50 nM) of inhibition MAOB/MAOA References

Propargylamine derivatives 6 Irreversible 233 95

Selegiline

Rasagiline 30 Irreversible 100 95

Allylamine derivatives 100 Irreversible 50 95

2-aminoethyl carboxamide 37 Reversible 26568 95

derivatives
Lazabemide

N-allenic indolalkylamine 25–25000 Irreversible >1 96

derivatives

4-substituted 120–260b Irreversible — 97

cubylcarbinyl amines

a
Ratio between MAO-B and MAO-A (IC50). High value indicates greater selectivity towards MAO-B.
b
Ki.

inhibitors, DA receptors undergo alterations seen in the MAO-
B knockout mice. However, changes in dopamine receptors
are not the sole effect of the MAO-B inhibitors. Recent studies
show the potential for an additional beneficial activity:
neuroprotection. Cumulative in vivo and in vitro evidence
points to the neuroprotective properties of propargylamine
MAO-B inhibitors, such as selegiline and rasagiline.(55–57)
MAO-B inhibitors and neuroprotection
in different neurotoxic models
Since PD progresses very slowly and over many years, its
diagnosis poses a tremendous challenge. Because the trigger
for dopaminergic cell death is unknown, the therapeutic
strategy in the last 15 years has been based on the DA
precursor levodopa, which raises the DA level. The adverse
effects of the treatment, the fact that this compound does
not arrest dopaminergic cell death and disease progression
and the possible contribution of apoptotic cell death to
Parkinson’s disease, prompted the search for new neuropro-
tective approaches. A neuroprotective therapeutic or disease-
modifying modality may be defined as an intervention that
delays or prevents neuronal cell death and thus affects
disease progression.
Selegiline aroused considerable interest as a potential
neuroprotective drug. As summarized in Tables 2 and 3,
preclinical studies point to the neuroprotective effect of the

BioEssays 26.1 83
Challenges

Table 2. Neuroprotective in vitro effects of MAO-B inhibitors selegiline and rasagiline

Neurotoxicity Neuroprotective
MAO-B Inhibitor Insult Model mechanism mechanism References

Selegiline Excitotoxicity Mesencephalic Depolarization and Yes 98

dopaminergic, primary calcium overload Independent of MAO-B
neurons
Hypocampal glia and Oxidative stress Yes, release of NGF 99
neurons
þ
MPP Dopaminergic neurons Oxidative stress Yes 100
mesencephalic and
striatal cells
BSO L-buthionine-(S,R)- Mesencephalic neurons Glutathione depletion Yes 101
sulfoximine Independent of MAO-B
Serum and NGF NGF-partially Oxidative stress and Yes 102
withdrawal differentiated rat growth factor Independent of
PC12 cells starvation MAO-B, induction
of transcription
Natural cell death Mesencephalic neurons Apoptosis and Yes 49
combined with serum oxidative stress Serum-enhanced 103
deprivation 104
Serum deprivation and E1A-NR3 immortalized Oxidative stress and Yesa 105
hypoxia retinal neurons hypoxia
SIN-1 Neuroblastoma Oxidative stress Yes 77
SH-SY5Y cells
Rasagiline Natural cell death Mesencephalic neurons Apoptosis and Yes 49
combined with serum oxidative stress Serum-enhanced 103
deprivation
SIN-1 Neuroblastoma Oxidative stress Yesb 75
SH-SY5Y cells 76
77
6-OHDA, SIN-1 Neuroblastoma SH-SY5Y Oxidative stress Yesb 76
cells Independent of MAO-B
N-methyl(R)salsolinol, Neuroblastoma Oxidative stress Yesb,c 106
6-OHDA, peroxynitrite SH-SY5Y cells Independent of MAO-B
N-methyl(R)salsolinol SH-SY5Y cells Oxidative stress Yesd 107
overexpressing Bcl-2
e
Serum and NGF Partially differentiated Free radical-induced Yes 48
withdrawal PC12 cells apoptosis
Oxidative stress Independent of MAO-B
OGD NGF-differentiated Oxygen-glucose Yes 57
PC12 cells deprivation Independent of MAO-B 60

a
Regulation of apoptosis-related gene expression.
b
Stabilization of mitochondrial potential.
c
Suppresion of caspases and DNA fragmentation.
d
Prevention of nuclear accumulation of GAPDH.
e
Increased gene expression of anti-apoptotic targets (proteins).

propargylamine MAO-B inhibitors selegiline and rasagiline.
This is illustrated by in vitro studies using a variety of
dopaminergic and nondopaminergic neurons taken from
different species and exposed to a range of neurotoxic insults
(excitotoxicity, oxidative stress, depolarization, growth factor
withdrawal and oxygen glucose deprivation). For example,
rasagiline prolongs the survival of cultured primary human and
rat DA neurons under serum-free conditions,(58) reduces
glutamate toxicity in hippocampal neurons,(59) protects nerve
growth factor (NGF)-differentiated pheochromocytoma PC12
cells from oxygen-glucose-deprivation (OGD-ischemia) in-
sult,(57,60) prevents deficits in behavioral parameters following
hypoxia in adult and senescent rats,(61) protects from experi-
mental focal ischemia in the rat,(62) and from closed head injury
in the mouse.(63) The last three are in vivo models. Although the
neuroprotective in vitro effect of selegiline, and even more so
of rasagiline, is clear-cut, the lack of reliable pathophysiological
models for the disease has led to some skepticism among the
Parkinson medical community. The PD models using neuronal
cultures treated with 1-methyl-4-phenyl pyridinium (MPPþ, a
metabolite of the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetra-
hydropyridine (MPTP)) and 6-hydroxydopamine (6-OH-DA)

84 BioEssays 26.1

Table 3. Neuroprotective in vivo effects of MAO-B inhibitors selegiline and rasagiline
MAO-B Inhibitor Insult Model
Selegiline Permanent or transient Rat
occlusion of cerebral artery Mouse
Gerbil
Selegiline Unilateral MPPþ neurotoxicity Sprague-Dawley rat
Rasagiline, Selegiline MPTP Monkey
Rasagiline Permanent middle cerebral Wistar rat
artery occlusion
Rasagiline Closed head injury Mouse
to trigger cell death, are the most common, and less
disputable. They are the main models used for screening
and developing novel drugs for PD treatment, although the
animals injected with the neurotoxin MPTP do not exhibit Lewy
bodies, a hallmark of PD.
While a variety of neurological deficits are triggered by the
above-mentioned insults in in vivo animal models, mainly the
MPTP model partially mimics the PD syndrome. In rats fed
selegiline, the lifespan of the animals was increased, in parallel
with enhanced catecholaminergic activity in the brain.(64,65)
This phenomenon was unrelated to MAO-B inhibition and
was a topic of controversy. The neuroprotective effects of the
MAO-B inhibitors selegiline and rasagiline have also been
investigated in mice, gerbils and monkeys (Table 3), in brain-
ischemia, head-trauma, and under MPTP toxicity. As opposed
to the clearly neuroprotective effects of propargylamines in
in vitro cellular systems and in vivo experimental animal
models, clinical studies with selegiline have failed to distin-
guish between the contribution of MAO-B inhibition and
MAO-B induced neuroprotection to the amelioration of clinical
symptoms.(66) Although selegiline delayed the need for levo-
dopa, its effect on disease progression has not been proved.
As for rasagiline, a placebo (control) study revealed that
patients with early PD who were treated with rasagiline for
12 months, showed less decline in neurological symptoms
(UPDRS score) than patients whose rasagiline treatment
was delayed for 6 months. These clinical results cannot be
explained by the purely symptomatic effect of rasagiline,(67)
and they may represent a neuroprotective effect.
Insights into the neuroprotection mechanism:
lack of correlation between neuroprotection
and MAO-B inhibition
The neuroprotective effect of propargylamines, demonstrated
in different insult models, both in vitro and in vivo, suggests that
it is not due to MAO inhibition (Tables 2 and 3). The finding that
propargylamines induce neuroprotection in neuronal cell
Challenges
Neurotoxicity Neuroprotective
mechanism mechanism References
Focal or whole Yes 99
brain ischemia 108
109
Oxidative stress Yes 110
Independent of MAO-B
Oxidative stress Yes 111
Brain ischemia Yes Independent of MAO-B 62
Mechanical brain Yes 48
trauma
cultures lacking MAO-B on the one hand, and the absence
of any neuroprotective effect by clorgyline, a MAO-A inhibitor,
on the other, also support the lack of correlation between
neuroprotection and MAO inhibition.(57) Furthermore, the
propargylamine concentration required for neuroprotection
both in vitro and in vivo is 1 mM, whereas the IC50 or Ki value for
in vitro MAO-B inhibition is in the range of 6–30 nM. As shown
in Tables 2 and 3, the major insults evoking neurotoxicity and,
in many cases, leading to neuronal apoptosis, are depolariza-
tion, calcium overload and oxidative stress. Conceptually,
therefore, the neuroprotective effect of propargylamines might
be grounded in the prevention of cell death or the activation of
pro-survival pathways minimizing cellular stress.
Rasagiline and selegiline exert their antioxidant effect
by upregulating the enzymes involved.(68) Selegiline(69) and
rasagiline,(70) promote free radical scavenging by activating
superoxide dismutase (SOD1 and SOD2) and catalase or by
increasing the SOD protein level,(71) upon chronic adminis-
tration to rats. In vitro experiments in our laboratory using cyclic
voltammetry further substantiated the antioxidant properties of
these compounds. Selegiline displays antioxidant effects
in vivo, which are probably not related to MAO-B inhibition
since selegiline reduced the free radical level at a pM con-
centrations too low to inhibit MAO-B activity.(72) The neuro-
protective effect of selegiline could also be mediated indirectly
via antagonistic modulation of the polyamine’s binding site on
the NMDA receptor, thereby reducing NMDA-receptor-gener-
ated excitotoxicity.(73) Moreover, rasagiline and selegiline act
directly as anti-apoptotic agents, probably by interfering with
the cellular apoptotic cascade (pro-survival) (Table 2). Several
studies have shown that treatment of cells with rasagiline
causes upregulation of putative anti-apoptotic and antioxidant
proteins such as Bcl-2, SOD, glutathione and BCLXL.(74) It has
been suggested that rasagiline protects cells from apoptosis
by stabilizing the mitochondrial membrane potential(75,76)
since such stabilization showed a causal relationship to inhibi-
tion of caspase activity and prevention of DNA fragmentation.
BioEssays 26.1 85
Challenges
In any event, the propargyl group of rasagiline and selegiline
is essential to MAO-B inhibition and the anti-apoptotic
effect.(77)
Molecular neuroprotective mechanism
of MAO-B inhibitors
The precise target and details of the molecular mechanisms
involved in the neuroprotective effect exerted by propargy-
lamines are not known. A major obstacle in mechanistic
studies on selegiline is that the molecule is largely (/80%)
converted into amphetamines, some of which display neuro-
toxic activity.(78) Cumulative evidence suggests that brain
injury following amphetamine and methamphetamine admin-
istration is due to increased free radical formation and mito-
chondrial damage, leading to a failure in cellular energy
metabolism followed by secondary excitotoxicity-induced
seizures.(78) The neuroprotective activity of selegiline derives
from a minor metabolite, desmethylselegiline (DMS), which
was shown to be neuroprotective in vitro.(79) However, the
amphetamine-like major metabolites may cause cell da-
mage(80) and thus could reverse the potential beneficial
effects of DMS. Indeed, the addition of L-methamphetamine
to oxygen–glucose-deprived PC-12 cells substantially in-
creased cell death.(57) When both L-methamphetamine and
selegiline were added to PC-12 cells exposed to OGD, the
protective effect of the latter was reduced.(57) In contrast to
selegiline, whose neuroprotective activity derives from its
minor metabolite, DMS, that of rasagiline is mediated solely by
the parent drug(57,81) and its major metabolite, 1-R-amino-
indan, is not toxic.(57)
An interesting attempt to identify the target of the propargy-
lamine anti-apoptotic effect was made by Kragten et al. in
1998.(82) They synthesized a selegiline derivative (CGP 3466)
that is neuroprotective but does not inhibit MAO and is not
metabolized to amphetamines. Using affinity binding, labeling
and BIAcore technology (in which CGP 3466 was covalently
bound to the surface of a flow cell with a CM5 sensor chip(82)),
they detected in rat brain lysates four protein bands of
38,43,50 and 299 kDa, all putative endogeneous binding sites
for CGP 3466. One of these proteins (38 kDa) was identified
as glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Using GAPDH antisense oligonucleotides, the investigators
established the importance of this enzyme in mediating the
neuroprotective effect of CGP 3466. Although the precise
role of GAPDH in neuronal apoptosis and in the neuroprotec-
tive mechanism of propargylamines awaits further investiga-
tion, GAPDH is the first selective target reported for these
compounds. GAPDH binds nicotinamide adenine dinucleotide
(NADþ)(82) at a site structurally similar to that of the flavin
adenine dinucleotide (FAD)-binding enzymes, to which MAO-
B belongs. Therefore, we propose that propargylamines bind
to GAPDH or other proteins with a tertiary structure similar to
that of the active site of MAO-B, thereby initiating an anti-
86 BioEssays 26.1
apoptotic process in the cells. It is very tempting to suggest
that the active site of these proteins possesses an FAD-
binding domain such as in MAO-B.(83) Recently, the structure
of human MAO-B was determined by crystalization at 3Å
resolution. Electron density analysis revealed that pargyline, a
selegiline analog, binds covalently to N5 of the flavine
nucleotide.(83) Therefore, it is conceivable that the insertion
of propargylamines into the FAD pocket(83) of certain proteins
with a structure similar to that of MAO-B will be followed by
covalent binding to FAD or NAD, as in MAO-B, resulting in
neuroprotection.
Hydrogen peroxide (H2O2), which is a by-product of the
enzymatic reaction catalyzed by MAO-B, has been shown to
inhibit GAPDH. This inactivates the glycolytic and mitochon-
drial pathways of ADP phosphorylation, resulting in a drop in
intracellular ATP level and cell death. It was shown that MAO-
B inhibition by propargylamines confers neuroprotection
from H2O2-induced injury due to GAPDH damage.(84) It
was recently demonstrated that the level of GAPDH and its
nuclear accumulation increase in apoptotic models of serum
withdrawal, growth factor deprivation and MPPþ-induced
neurotoxicity, pointing to the enzyme’s essential role in apop-
tosis.(85,86) Furthermore, propargylamines prevented both
these phenomena, suggesting that this activity rather than
MAO-B inhibition, may contribute to the neuroprotective
effect.(85) Another important finding was the subcellular redu-
ction in GAPDH activity in Alzheimer’s disease and Hunting-
ton’s disease.(87) The investigators posited that intracellular
formation of complexes between GAPDH and proteins chara-
cteristic of neurodegenerative disorders, such as a-synuclein
in PD, b-amyloid in Alzheimer’s or huntingtin in Huntington’s,
may represent an emerging cellular phenotype of neurode-
generative disorders The major challenges in this field will be
to further clarify the apoptotic role of GAPDH, the pathophy-
siological meaning of GAPDH complexes, to identify novel
anti-apoptotic and/or pro-survival FAD- or NAD-binding
proteins and to delineate the interaction between these novel
enzymes and propargylamines in neuroprotection.
Neuroprotection strategy perspectives
In the present review, we have focused on the neuroprotection
of MAO-B inhibitors, their chemical characterization and their
cellular and molecular mechanisms of action. It is impossible in
so brief a review to cite all the earlier work recently summarized
by Magyar and Vizi.(88) We have included a few examples to
illustrate the newly emerging apoptotic concept of dopami-
nergic neuronal degeneration and have described selected
studies on the neuroprotective contribution of MAO-B inhi-
bitors such as propargylamines. The majority of in vitro and
in vivo PD studies attribute the neurodegeneration of SN
dopaminergic neurons to a long series of insults such as:
mitochondrial impairment and oxidative stress, Ca2þ overload,
iron metabolism, neurotoxins, excitotoxicity, neurotrophins,

oxygen and glucose deprivation, depolarization and inflam-
mation. It is conceivable that the neuroprotective effect
of propargylamines is due to a shift in the neurotoxicity-
neuroprotection balance towards survival (Fig. 1). MAO-B,
GAPDH and other FAD/NAD-binding proteins represent
pivotal targets of the balance, as reflected by the neuropro-
tective effect of selegiline and rasagiline. Therefore, a pharma-
ceutical approach towards neuroprotection would be to
synthesize novel MAO-B/GAPDH inhibitors. Such inhibitors
should help to launch mechanistic studies aimed at elucidating
the molecular interactions of these compounds in anti-apo-
ptotic and/or survival signaling pathways. A crucial need in PD
drug development is the establishment of new in vitro and
in vivo models of the disease. Once these models are avail-
able, it will be necessary to identify neuronal dopaminergic
apoptotic pathways, as well as survival pathways. One of the
most remarkable changes recently observed in the nigro-
striatal region of the PD brain is the decreased level of neuro-
trophins supporting dopaminergic neuron survival, such
as brain-derived neurotrophic factor (BDNF), NGF(89) and
glial-derived neurotrophic factor (GDNF).(90) Therefore, re-
combinant neurotrophins or compounds increasing the local
production of neurotrophins,(91) and/or neurotrophin receptor-
Challenges
agonists could prove beneficial in the treatment of this
disorder. Development of MAO-B inhibitors with neurotro-
phin-like activity may be a future strategy in PD therapy. This
possibility is supported by the recent finding that rasagiline
increases GDNF production and release by neuroblastoma
cells.(92) Despite the uncertainties and difficulties attendant
upon neuroprotective therapy in PD, clinical trials with innovat-
ive neuroprotective agents must proceed for neuroprotection
to become a reality.
In addition to the use of low molecular weight drugs for PD
treatment, modern therapeutic tactics focus on cell and gene
therapy. Cell therapy includes implantation in the SN of em-
bryonic or neuronal stem cells, which can synthesize and
release dopamine to correct the PD syndrome.(93) Gene
therapy in PD should aim both at supplementing the low SN
dopamine level by introducing the genes encoding dopamine-
synthesizing enzymes into non-dopaminergic cells in the
striatum, and at supporting the survival of dopaminergic
neurons by preventing apoptosis through the introduction of
genes blocking this process.(94)
We anticipate that, in coming years, the cellular pathophy-
siology of Parkinson’s disease will be clarified, allowing the
design of new drugs and novel therapeutic approaches.
Figure 1. Schematic depicting the balance be-
tween neurotoxicity and neuroprotection in Par-
kinson’s disease. Upper part: Normal population of
SN dopaminergic neurons, consisting mainly of
live neurons (blue) and a few dead neurons (red).
Enzymes (green) (targeted by propargylamines)
pivot the balance between cell survival (#) and cell
death ("). Insults shift the balance towards
neurotoxicity; rasagiline and selegiline tip the
balance towards neuroprotection.
BioEssays 26.1 87
Challenges
References
1. Sethi KD. Clinical aspects of Parkinson’s disease. Curr Opin Neurol
2002;15:457–460.
2. Hornykiewicz O, Kish SJ. Biochemical pathophysiology of Parkinson’s
disease. Adv Neurol 1987;45:19–34.
3. Jellinger K. Pathology of Parkinson’s syndrome. In: Calne DB, editor.
Handbook of Experimental Pharmacology. Berlin: Springer-Verlag; 1989.
p 47–112.
4. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F.
Brain dopamine and the syndromes of Parkinson and Huntington. Clini-
cal, morphological and neurochemical correlations. J Neurol Sci 1973;
20:415–455.
5. Riess O, Kuhn W, Krüger R. Genetic influence on the development of
Parkinson’s disease. J Neurol 2000;247:69–74.
6. Yahr MD, Bergman KJ. Advances in Neurology. New York: Raven Press;
1986. p 317–321.
7. Tanner CM. The role of environmental toxins in the etiology of Parkinson’s
disease. TINS 1989;12:49–54.
8. Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson’s disease.
Evidence supporting it. Ann Neurol 1992;32:804–812.
9. Gerlach M, Riederer P, Youdim MBH. Molecular mechanism for
neurodegeneration: synergism between reactive oxygen species,
calcium and excitotoxic amino acids. In: Battistin L, Scarlato G, Caraceni
T, Ruggieri S, editors. Advances in Neurology. Philadelphia: Lippincott-
Raven; 1996. p 177–194.
10. Headley PM, Grillner S. Excitatory amino acid neurotoxicity and synaptic
transmission: the evidence for a physiological function. In: Lodge D,
Collingridge G, editors. The pharmacology of excitatory amino acids: A
TIPS special report. Cambridge: Elsevier; 1990. p 30–36.
11. De Erausquin GA, Costa E, Hanbauer I. Calcium homoestasis, free
radical formation, and trophic factor dependence mechanisms in
Parkinson’s disease. Pharmacol Rev 1994;46:467–482.
12. Beal MF. Ageing, energy, and oxidative stress in neurodegenerative
diseases. Ann Neurol 1995;38:357–366.
13. Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH. Altered brain
metabolism of iron as a cause of neurodegenerative diseases?
J Neurochem 1994;63:793–807.
14. Thompson CB. Apoptosis in the pathogenesis and treatment of disease.
Science 1995;267:1456–1462.
15. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima
S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause
autosomal recessive juvenile parkinsonism. Nature 1998;392:605–
608.
16. Leroy E, et al. The ubiquitin pathway in Parkinson’s disease. Nature
1998;392:451–452.
17. Polymeropoulos MH, et al. Mutation in the alpha-synuclein gene
identified in families with Parkinson’s disease. Science 1997;276:2045–
2047.
18. Mandel S, Weinreb O, Youdim MB. Using cDNA microarray to assess
Parkinson’s disease models and the effects of neuroprotective drugs.
TIPS 2003;24:184–191.
19. Momose Y, Murata M, Kobayashi K, Tachikawa M, Nakabayashi Y,
Kanazawa I, Toda T. Association studies of multiple candidate genes for
Parkinson’s disease using single nucleotide polymorphisms. Ann Neurol
2002;51:133–136.
20. Ceballos-Baumann AO. Functional imaging in Parkinson’s disease: acti-
vation studies with PET, fMRI and SPECT. J Neurol 2003;250(Suppl 1):
I15–I23.
21. Mochizuki H, Goto K, Mon H, Mizuno Y. Histochemical detection of
apoptosis in Parkinson’s disease. J Neurol Sci 1996;137:120–123.
22. Oppenheim RW, Flavell RA, Vinsant S, Prevette D, Kuan CY, Rakic P.
Programmed cell death of developing mammalian neurons after genetic
deletion of caspases. J Neurosci 2001;21:4752–4760.
23. Hartmann A, et al. Caspase-3: A vulnerability factor and final effector in
apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc
Natl Acad Sci USA 2000;97:2875–2880.
24. Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H,
Nagatsu T. Caspase activities and tumor necrosis factor receptor R1
(p55) level are elevated in the substantia nigra from parkinsonian brain.
J Neural Transm 2000;107:335–341.
88 BioEssays 26.1
25. Tatton NA. Increased caspase 3 and Bax immunoreactivity accompany
nuclear GAPDH translocation and neuronal apoptosis in Parkinson’s
disease. Exp Neurol 2000;166:29–43.
26. Clarke G, Collins RA, Leavitt BR, Andrews DF, Hayden MR, Lumsden CJ,
McInnes RR. A one-hit model of cell death in inherited neuronal
degenerations. Nature 2000;406:195–199.
27. Wullner U, Kornhuber J, Weller M, Schulz JB, Loschmann PA, Riederer P,
Klockgether T. Cell death and apoptosis regulating proteins in
Parkinson’s disease—a cautionary note. Acta Neuropathol 1999;97:
408–412.
28. Kosel S, Egensperger R, von Eitzen U, Mehraein P, Graeber MB. On the
question of apoptosis in the parkinsonian substantia nigra. Acta
Neuropathol (Berl) 1997;93:105–108.
29. Jellinger KA, Stadelmann CH. The enigma of cell death in neurodegen-
erative disorders. J Neural Transm Suppl 2000;60:21–36.
30. Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic
nigral neurons in long-standing Parkinson’s disease. Mov Disord 1998;
13:221–227.
31. Rajput AH, Fenton ME, Birdi S, Macaulay R, George D, Rozdilsky B, Ang
LC, Senthilselvan A, Hornykiewicz O. Clinical-pathological study of
levodopa complications. Mov Disord 2002;17:289–296.
32. Hristova AH, Koller WC. Early Parkinson’s disease: what is the best
approach to treatment. Drugs Aging 2000;17:165–181.
33. Yu PH, Tipton KF. Deuterium isotope effect of phenelzine on the inhibition
of rat liver mitochondrial monoamine oxidase activity. Biochem Pharma-
col 1989;38:4245–4251.
34. Davis DS, Tasuhara H, Boobis AR, George CF. The effects of reversible
inhibitors of monoamine oxidase on tyramine deamination in dog intes-
tine. In: Tipton KF, Dostert P, Strolin-Benedetti M, editors. Monoamine
Oxidase and Disease. London: Academic Press; 1984. p 443–448.
35. Hasan F, McCrodden JM, Kennedy NP, Tipton KF. The involvement of
intestinal monoamine oxidase in the transport and metabolism of
tyramine. J Neural Transm 1988;26(Suppl):1–9.
36. Blackwell B. Hypertensive crisis due to monoamine oxidase inhibitors.
Lancet 1963;ii:849–851.
37. Blackwell B, Marley E, Price J. Hypertensive interactions between
monoamine oxidase inhibitors and food stuffs. Br J Psychiatry 1967;113:
349–365.
38. Johnston JP. Some observations upon a new inhibitor of monoamine
oxidase in the brain tissue. Biochem Pharmacol 1968;17:1285–1297.
39. Parkinson Study Group. Effects of deprenyl on the progression of
disability in early Parkinson’s disease. New Engl J Med 1989;321:1364–
1371.
40. Parkinson Study Group. A controlled trial of rasagiline in early Parkinson’s
disease: the TEMPO Study. Arch Neurol 2002;59:1937–1943.
41. Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW,
Seeburg PH, Shih JC. cDNA cloning of human liver monoamine oxidase
A and B: molecular basis of differences in enzymatic properties. Proc
Natl Acad Sci USA 1988;85:4934–4938.
42. Hsu YP, Weyler W, Chen S, Sims KB, Rinehart WB, Utterback MC, Powell
JF, Breakefield XO. Structural features of human monoamine oxidase A
elucidated from cDNA and peptide sequences. J Neurochem 1988;51:
1321–1324.
43. Chen ZY, et al. Structure of the human gene for monoamine oxidase type
A. Nucleic Acids Res 1991;19:4537–4541.
44. Shih JC, Chen K, Ridd MJ. Monoamine Oxidase: From Genes to
Behavior. Annu Rev Neurosci 1999;22:197–217.
45. Hall TR, Uruena G. Pharmacology and physiology of monoamine oxidase
activity in vertebrates—a comparative study. Comp Biochem Physiol B
1983;76:393–397.
46. Parkinson Study Group. Effect of lazabemide on the progression of
disability in early Parkinson’s disease. Ann Neurol 1996;40:99–107.
47. Birkmayer W, Riederer P, Youdim MB, Linauer W. The potentiation of the
anti-akinetic effect after L-dopa treatment by an inhibitor of MAO-B,
Deprenyl. J Neural Transm 1975;36:303–326.
48. Finberg JP, Lamensdorf I, Commissiong JW, Youdim MB. Pharmacology
and neuroprotective properties of rasagiline. J Neural Transm 1996;48:
95–101.
49. Youdim MBH, Wadia A, Tatton W, Weinstock M. The anti-Parkinson
drug rasagiline and its cholinesterase inhibitor derivatives exert

neuroprotection unrelated to MAO inhibition in cell culture and in vivo.
Ann NY Acad Sci 2001;939:450–458.
50. Speiser Z, Levy R, Cohen S. Effects of N-propargyl-1-(R)aminoindan
(rasagiline) in models of motor and cognition disorders. J Neural Transm
1998;Suppl 52:287–300.
51. Youdim MB, Finberg JP. Pharmacological actions of l-deprenyl (selegi-
line) and other selective monoamine oxidase B inhibitors. Clin Pharmacol
Ther 1994;56:725–733.
52. Chen L, He M, Sibille E, Thompson A, Sarnyai Z, Baker H, Shippenberg
T, Toth M. Adaptive changes in postsynaptic dopamine receptors
despite unaltered dopamine dynamics in mice lacking monoamine
oxidase B J Neurochem 1999;73:647–655.
53. Garrick NA, Murphy DL. Species differences in the deamination of
dopamine and other substrates for monoamine oxidase in brain.
Psychopharmacology 1980;72:27–33.
54. Lenders JWM, et al. Specific genetic deficiencies of the A and B
isoenzymes of monoamine oxidase are characterized by distinct neuro-
chemical and clinical phenotypes. J Clin Invest 1996;97:1010–1019.
55. Finnegan KT, Skratt JJ, Irwin I, DeLanney LE, Langston JW. Protection
against DSP-4-induced neurotoxicity by deprenyl is not related to its
inhibition of MAO B. Eur J Pharmacol 1990;184:119–126.
56. Yu PH, Davis BA, Fang J, Boulton AA. Neuroprotective effects of some
monoamine oxidase-B inhibitors against DSP-4-induced noradrenaline
depletion in the mouse hippocampus. J Neurochem 1994;62:697–704.
57. Abu-Raya S, Tabakman R, Blaugrund E, Trembovler V, Lazarovici P.
Neuroprotective and neurotoxic effects of monoamine oxidase-B
inhibitors and derived metabolites under ischemia in PC12 cells. Eur J
Pharmacol 2002;434:109–116.
58. Goggi J, Theofilopoulos S, Riaz SS, Jauniaux E, Stern GM, Bradford HF.
The neuronal survival effects of rasagiline and deprenyl on fetal human
and rat ventral mesencephalic neurons in culture. Neuroreport
2000;11:3937–3941.
59. Yoles E, Shwartz M. N-Propargyl-1 (R)-aminoindan (TVP-1012), a
putative neuroprotective agent, enhances in vitro neuronal survival after
glutamate toxicity. Proc Am Soc Neurosci 1995;21:562.
60. Abu-Raya S, Blaugrund E, Trembovler V, Shilderman-Bloch E, Shohami
E, Lazarovici P. Rasagiline, a monoamine oxidase-B inhibitor, protects
NGF-differentiated PC12 cells against oxygen-glucose deprivation.
J Neurosci Res 1999;58:456–463.
61. Speiser Z, Katzir O, Rehavi M, Zabarski T, Cohen S. Sparing by
rasagiline (TVP-1012) of cholinergic functions and behavior in the
postnatal anoxia rat. Pharmacol Biochem Behav 1998;60:387–393.
62. Speiser Z, Mayk A, Eliash S, Cohen S. Studies with rasagiline, a MAO-B
inhibitor, in experimental focal ischemia in the rat. J Neural Transm
1999;106:593–606.
63. Huang W, Chen Y, Shohami E, Weinstock M. Neuroprotective effect of
rasagiline, a selective monoamine oxidase-B inhibitor, against closed
head injury in the mouse. Eur J Pharmacol 1999;366:127–135.
64. Knoll J, Miklya I. Enhanced catecholaminergic and serotoninergic
activity in rat brain from weaning to sexual maturity: rationale for
prophylactic (-)deprenyl (selegiline) medication. Life Sci 1995;56:611–
620.
65. Knoll J. The pharmacology of selegiline ((-)deprenyl). New aspects. Acta
Neurol Scand Suppl 1989;126:83–91.
66. Parkinson Study Group. Effect of tocopherol and deprenyl on the
progression of disability in early Parkinson’s disease. New Engl J Med
1989;328:176–183.
67. Siderowf A, and the Parkinson Study Group. Earlier treatment with
rasagiline may attenuate (UPDRS) progression of PD. Movement
Disorders 2001;16:981.
68. Kitani K, Kanai S, Ivy GO, Carrillo MC. Pharmacological modifications of
endogenous antioxidant enzymes with special reference to the effects of
deprenyl: a possible antioxidant strategy. Mech Ageing Dev 1999;111:
211–221.
69. Kitani K, Miyasaka K, Kanai S, Carrillo MC, Ivy GO. Upregulation of
antioxidant enzyme activities by deprenyl. Implications for life span
extension. Ann N Y Acad Sci 1996;786:391–409.
70. Carrillo MC, Kanai S, Nokubo M, Kitani K. (-) deprenyl induces activities
of both superoxide dismutase and catalase but not of glutathione
peroxidase in the striatum of young male rats. Life Sci 1991;48:517–521.
Challenges
71. Lai CT, Zuo DM, Yu PH. Is brain superoxide dismutase activity increased
following chronic treatment with 1-deprenyl? J Neural Transm Suppl
1994;41:221–229.
72. Wu RM, Chiuech CC, Pert A, Murphy DL. Apparent antioxidant effect of
L-deprenyl on hydroxyl radical formation and nigral injury elicited by
MPPþ in vivo. Eur J Pharmacol 1993;243:241–248.
73. Gerlach M, Desser H, Youdim MB, Riederer P. New horizons in molecular
mechanisms underlying Parkinson’s disease and in our understanding of
the neuroprotective effects of selegiline. J Neural Transm Suppl 1996;48:
7–21.
74. Naoi M, Maruyama W, Youdium MBH. Molecular mechanism underlying
neuroprotection by rasagiline. J Neurochem 2002;81:4.
75. Maruyama W, Yamamoto T, Kitani K, Carrillo MC, Youdim M, Naoi M.
Mechanism underlying anti-apoptotic activity of a (-) deprenyl-related
propargylamine, rasagiline. Mech Ageing Dev 2000;116:181–191.
76. Maruyama W, Takahashi T, Youdim M, Naoi M. The anti-Parkinson drug,
rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in
human dopaminergic neuroblastoma SH-SY5Y cells. J Neural Transm
2002;109:467–481.
77. Maruyama W, Naoi M. Neuroprotection by (-)-deprenyl and related
compounds. Mech Ageing Dev 1999;111:189–200.
78. Bowyer JF, Peterson SL. Neuronal degeneration in the forebrain
produced by amphetamine, methamphetamine and fenfluramine. In:
Lester DS, Slikker W Jr, Lazarovici P, editors. Cellular and Molecular
Mechanisms of Toxin Action: Site-Selective Neurotoxicity. London: Taylor
and Francis; 2002. p 207–232.
79. Mytilineou C, Radcliffe PM, Olanow CW. L-(-)-desmethylselegiline, a
metabolite of selegiline [L-(-)-deprenyl], protects mesencephalic dopa-
mine neurons from excitoxicity in vitro. J Neurochem 1997;68:434–
436.
80. Oh C, Murray B, Bhattacharya N, Holland D, Tatton WG. (-)-Deprenyl
alters the survival of adult murine facial motoneurons after axotomy:
increases in vulnerable C57BL strain but decreases in motor neuron
degeneration mutants. J Neurosci Res 1994;38:64–74.
81. Maruyama W, Youdim MBH, Naoi M. Antiapoptotic properties of
rasagiline N-propargylamine-1(R)-aminoindan, and its optical (S)-iso-
mer, TV1022. Ann NY Acad Sci 2001;939:320–329.
82. Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler P, Müller D,
Van Oostrum J, Waldmeier P, Fürst P. Glyceraldehyde-3-phosphate
dehydrogenase, the putative target of the anti-apoptotic compounds
CGP 3466 and R-(-)-deprenyl. J Biol Chem 1998;273:5821–5828.
83. Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, Mattevi A.
Structure of human monoamine oxidase B, a drug target for the treatment
of neurological disorders. Nat Struct Biol 2002;9:22–26.
84. Hyslop PA, Hinshaw DB, Halsey WA Jr, Schraufstatter IU, Sauerheber
RD, Spragg RG, Jackson JH, Cochrane CG. Mechanisms of oxidant-
mediated cell injury. The glycolytic and mitochondrial pathways of ADP
phosphorylation are major intracellular targets inactivated by hydrogen
peroxide. J Biol Chem 1988;263:1665–1675.
85. Carlile GW, Chalmers-Redman RM, Tatton NA, Pong A, Borden KE,
Tatton WG. Reduced apoptosis after nerve growth factor and serum
withdrawal: conversion of tetrameric glyceraldehyde-3-phosphate dehy-
drogenase to a dimer. Mol Pharmacol 2000;57:2–12.
86. Fukuhara Y, Takeshima T, Kashiwaya Y, Shimoda K, Ishitani R,
Nakashima K. GAPDH knockdown rescues mesencephalic dopaminer-
gic neurons from MPPþ-induced apoptosis. Neuroreport 2001;12: 2049–
2052.
87. Mazzola JL, Sirover MA. Alteration of intracellular structure and function
of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype
of neurodegenerative disorders? Neurotoxicology 2002;23:603–609.
88. Magyar K, Vizi ES. Milestones in monoamine oxidase research: dis-
covery of (-)-deprenyl. Budapest: Medicina Publishing House Co; 2000.
89. Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H,
Nagatsu T. Brain-derived growth factor and nerve growth factor
concentrations are decreased in the substantia nigra in Parkinson’s
disease. Neurosci Lett 1999;270:45–48.
90. Brundin P. GDNF treatment in Parkinson’s disease: time for controlled
clinical trials? Brain 2002;125:2149–2151.
91. Yamaguchi K, Sasano A, Urakami T, Tsuji T, Kondo K. Stimulation of
nerve growth factor production by pyrroloquinoline quinone and its
BioEssays 26.1 89
Challenges
derivatives in vitro and in vivo. Biosci Biotechnol Biochem 1993;57:
1231–1233.
92. Maruyama W. Neuroprotection by propargylamines in PD Suppression of
apoptosis and induction of prosurvival genes Neurotoxicol and Teratol
2002;4:675–682.
93. Zigova T, Snyder EY, Sanberg PR. Neural Stem Cells for Brain and Spinal
Cord Repair. Totowa: Humana Press; 2003.
94. Nagatsu T. Parkinson’s disease: changes in apoptosis-related factors
suggesting possible gene therapy. J Neural Transm 2002;109:731–745.
95. Bentue-Ferrer D, Menard G, Allain H. Monoamine oxidase B inhibitors:
current status and future potential. CNS drugs 1996;6:217–236.
96. Perez V, Marco JL, Fernandez-Alvarez E, Unzeta M. Kinetic studies of N-
allenic analogues of tryptamine as monoamine oxidase inhibitors. J
Pharm Pharmacol 1996;48:718–722.
97. Zhou JP, Li J, Upadhyaya S, Eaton PE, Silverman RB. 4-substituted
cubylcarbinylamines: a new class of mechanism-based monoamine
oxidase B inactivators. J Med Chem 1997;40:1165–1168.
98. Mytilineou C, Radcliffe PM, Olanow CW. L-(-)-Desmethylselegiline, a
metabolite of selegiline [L-(-)-Deprenyl], protects mesencephalic dopa-
mine neurons from excitotoxicity in vitro. J Neurochem 1997;68:434–436.
99. Semkova I, Wolz P, Schilling M, Krieglstein J. Selegiline enhances NGF
synthesis and protects central nervous system neurons from excitotoxic
and ischemic damage. Eur J Pharmacol 1996;315:19–30.
100. Koutsilieri E, Chen TS, Rausch WD, Riederer P. Selegiline is neuropro-
tective in primary brain cultures treated with 1-methyl-4-phenylpyridi-
nium. Europ J Pharmacol 1996;306:181–186.
101. Mytilineou C, Leonardi EK, Radcliffe P, Heinonen EH, Han SK, Werner P,
Cohen G, Olanow CW. Deprenyl and desmethylselegiline protect
mesencephalic neurons from toxicity induced by glutathione depletion.
J Pharmacol Exp Therap 1998;284:700–706.
102. Tatton WG, Ju WY, Holland DP, Tai C, Kwan M. (-)-Deprenyl reduces
PC12 cell apoptosis by inducing new protein synthesis. J Neurochem
1994;63:1572–1575.
90 BioEssays 26.1
103. Finberg JP, Takeshima T, Johnston JM, Commissiong JW. Increased
survival of dopaminergic neurons by rasagiline, a monoamine oxidase B
inhibitor. NeuroReport 1998;9:703–707.
104. Roy E, Bedard PJ. Deprenyl increases survival of rat foetal nigral neurons
in culture. NeuroReport 1993;4:1183–1186.
105. Xu L, Ma J, Seigel GM, Ma J. L-deprenyl, blocking apoptosis and
regulating gene expression in cultured retinal neurons. Biochem
Pharmacol 1999;58:1183–1190.
106. Maruyama W, Akao Y, Youdim MB, Naoi M. Neurotoxins induce
apoptosis in dopamine neurons: protection by N-propargylamine-1(R)-
and (S)-aminoindan, rasagiline and TV1022. In: Riederer P, Calne DB,
Horowski R, Mizuno Y, Olanow CW, Poewe W, Youdim MBH, editors.
Advances in Research on Neurodegeneration. Wien: Springer-Verlag;
2000. p 171–186.
107. Maruyama W, Akao Y, Youdim MB, Davis BA, Naoi M. Transfection-
enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline,
prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydro-
genase induced by an endogenous dopaminergic neurotoxin, N-methyl
(R) salsolinol. J Neurochem 2001;78:727–735.
108. Lahtinen H, Koistinaho J, Kauppinen R, Haapalinna A, Keinänen R,
Sivenius J. Selegiline treatment after transient global ischemia in gerbils
enhances the survival of CA1 pyramidal cells in the hippocampus. Brain
Res 1997;757:260–267.
109. Knollema S, Aukema W, Hom H, Korf J, Ter Horst GJ. L-deprenyl
reduces brain damage in rats exposed to transient hypoxia-ischemia.
Stroke 1995;26:1883–1887.
110. Wu RM, Chen RC, Chiueh CC. Effect of MAO-B inhibitors on MPPþ
toxicity in vivo. Ann NY Acad Sci 2000;899:255–261.
111. Kupsch A, Sautter J, Gotz ME, Breithaupt W, Schwarz J, Youdim MBH,
Riederer P, Gerlach M, Oertel WH. Monoamine oxidase-inhibition and
MPTP-induced neurotoxicity in the non-human primate: comparison of
rasagiline (TVP 1012) with selegiline. J Neural Transm 2001;108:985–
1009.