Review (1) - 2004 - Tabakmna Et Al

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 characterized by a combination of rigidity, poverty of movement, tremor and postural instability. Selegiline is a selective and irreversible propargylamine type B monoamine oxidase (MAO-B) inhibitor. This drug, which inhibits 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, rasagiline, 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: [email protected] 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, brainderived neurotrophic factor; NGF, nerve growth factor; GDNF, glial derived neurotrophic factor; DMS, desmethylselegiline; MPPþ, 1methyl-4-phenyl pyridinium; MPTP, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 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 mechanism of propargylamines indicate that glyceraldehyde-3phosphate 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 (hypokinesia).(1) For many years, it has been known that PD syndrome 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 characterized 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 degeneration (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 contributions 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.

Challenges

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 tomography (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 monoamine 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 neuroprotective 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 additional 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 neurodegenerative 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-3phosphate 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 deteriorate 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 accelerated 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)

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 following 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 dopaminergic 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 synthesized in the 1950s, was used as antidepressants due to their inhibitory effect on the metabolism of monoamine neurotransmitters. These inhibitors are both irreversible and non-selective. 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 normally 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 ameliorate 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 neurotransmitters (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 physiological 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 homologous 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, MAOA 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, norepinephrine and epinephrine, whereas MAO-B metabolizes dopamine and phenylethylamine.(44) Both MAO-B and MAOA 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 potential of each isoform. Inhibition of MAO activity in the brain increases the synaptic level of the neurotransmitters serotonin, 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 compound 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-deprenyl) (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, absorbed 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 monotherapy 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 underlies 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 encoding 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 accumbens.(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 (IC50 nM)

Mechanism of inhibition

Selectivitya MAOB/MAOA

References

Propargylamine derivatives Selegiline

6

Irreversible

233

95

Rasagiline

30

Irreversible

100

95

Allylamine derivatives

100

Irreversible

50

95

2-aminoethyl carboxamide derivatives Lazabemide

37

Reversible

26568

95

N-allenic indolalkylamine derivatives

25–25000

Irreversible

>1

96

4-substituted cubylcarbinyl amines

120–260b

Irreversible

—

97

Chemical group

Chemical structure

a

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

b

inhibitors, DA receptors undergo alterations seen in the MAOB 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 neuroprotective approaches. A neuroprotective therapeutic or diseasemodifying 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 MAO-B Inhibitor Selegiline

Insult Excitotoxicity

þ

MPP

BSO L-buthionine-(S,R)sulfoximine Serum and NGF withdrawal

Natural cell death combined with serum deprivation Serum deprivation and hypoxia SIN-1 Rasagiline

Natural cell death combined with serum deprivation SIN-1

6-OHDA, SIN-1 N-methyl(R)salsolinol, 6-OHDA, peroxynitrite N-methyl(R)salsolinol Serum and NGF withdrawal OGD

Model Mesencephalic dopaminergic, primary neurons Hypocampal glia and neurons Dopaminergic neurons mesencephalic and striatal cells Mesencephalic neurons

Neurotoxicity mechanism

Neuroprotective mechanism

References

Depolarization and calcium overload

Yes Independent of MAO-B

98

Oxidative stress

Yes, release of NGF

99

Oxidative stress

Yes

100

Glutathione depletion

Yes Independent of MAO-B Yes Independent of MAO-B, induction of transcription Yes Serum-enhanced

101 102

NGF-partially differentiated rat PC12 cells

Oxidative stress and growth factor starvation

Mesencephalic neurons

Apoptosis and oxidative stress

E1A-NR3 immortalized retinal neurons Neuroblastoma SH-SY5Y cells Mesencephalic neurons

Oxidative stress and hypoxia Oxidative stress

Yesa

49 103 104 105

Yes

77

Apoptosis and oxidative stress

Yes Serum-enhanced

Neuroblastoma SH-SY5Y cells

Oxidative stress

Yesb

Neuroblastoma SH-SY5Y cells Neuroblastoma SH-SY5Y cells SH-SY5Y cells overexpressing Bcl-2 Partially differentiated PC12 cells

Oxidative stress

Yesb Independent of MAO-B Yesb,c Independent of MAO-B Yesd

NGF-differentiated PC12 cells

Oxidative stress Oxidative stress Free radical-induced apoptosis Oxidative stress Oxygen-glucose deprivation

Yes

e

Independent of MAO-B Yes Independent of MAO-B

49 103 75 76 77 76 106 107 48

57 60

a

Regulation of apoptosis-related gene expression. 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). b

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-

84

BioEssays 26.1

sult,(57,60) prevents deficits in behavioral parameters following hypoxia in adult and senescent rats,(61) protects from experimental 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-tetrahydropyridine (MPTP)) and 6-hydroxydopamine (6-OH-DA)

Challenges

Table 3. Neuroprotective in vivo effects of MAO-B inhibitors selegiline and rasagiline MAO-B Inhibitor

Neurotoxicity mechanism

Neuroprotective mechanism

Insult

Model

Selegiline

Permanent or transient occlusion of cerebral artery

Focal or whole brain ischemia

Yes

Selegiline

Unilateral MPPþ neurotoxicity

Rat Mouse Gerbil Sprague-Dawley rat

Oxidative stress

Rasagiline, Selegiline Rasagiline

MPTP Permanent middle cerebral artery occlusion Closed head injury

Monkey Wistar rat

Oxidative stress Brain ischemia

Yes Independent of MAO-B Yes Yes Independent of MAO-B

Mouse

Mechanical brain trauma

Rasagiline

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 brainischemia, 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 distinguish 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 levodopa, 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

Yes

References 99 108 109 110 111 62 48

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 depolarization, 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 administration 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 concentrations too low to inhibit MAO-B activity.(72) The neuroprotective 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-generated 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 inhibition 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 propargylamines 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 neurotoxic activity.(78) Cumulative evidence suggests that brain injury following amphetamine and methamphetamine administration is due to increased free radical formation and mitochondrial 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 damage(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 increased 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-aminoindan, is not toxic.(57) An interesting attempt to identify the target of the propargylamine 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 neuroprotective mechanism of propargylamines awaits further investigation, 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 MAOB 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 FADbinding domain such as in MAO-B.(83) Recently, the structure ˚ of human MAO-B was determined by crystalization at 3A 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 mitochondrial pathways of ADP phosphorylation, resulting in a drop in intracellular ATP level and cell death. It was shown that MAOB 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 apoptosis.(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 reduction in GAPDH activity in Alzheimer’s disease and Huntington’s disease.(87) The investigators posited that intracellular formation of complexes between GAPDH and proteins characteristic 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 neurodegenerative disorders The major challenges in this field will be to further clarify the apoptotic role of GAPDH, the pathophysiological 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 dopaminergic neuronal degeneration and have described selected studies on the neuroprotective contribution of MAO-B inhibitors 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,

Challenges

oxygen and glucose deprivation, depolarization and inflammation. It is conceivable that the neuroprotective effect of propargylamines is due to a shift in the neurotoxicityneuroprotection balance towards survival (Fig. 1). MAO-B, GAPDH and other FAD/NAD-binding proteins represent pivotal targets of the balance, as reflected by the neuroprotective effect of selegiline and rasagiline. Therefore, a pharmaceutical 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-apoptotic 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 available, 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 nigrostriatal region of the PD brain is the decreased level of neurotrophins supporting dopaminergic neuron survival, such as brain-derived neurotrophic factor (BDNF), NGF(89) and glial-derived neurotrophic factor (GDNF).(90) Therefore, recombinant neurotrophins or compounds increasing the local production of neurotrophins,(91) and/or neurotrophin receptor-

agonists could prove beneficial in the treatment of this disorder. Development of MAO-B inhibitors with neurotrophin-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 innovative 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 embryonic 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 dopaminesynthesizing 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 pathophysiology of Parkinson’s disease will be clarified, allowing the design of new drugs and novel therapeutic approaches.

Figure 1. Schematic depicting the balance between neurotoxicity and neuroprotection in Parkinson’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. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973; 20:415–455. 5. Riess O, Kuhn W, Kru¨ger 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: LippincottRaven; 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: activation 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 neurodegenerative 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 Pharmacol 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 intestine. 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

Challenges

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 (selegiline) 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 neurochemical 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.

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 dopamine 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)-isomer, TV1022. Ann NY Acad Sci 2001;939:320–329. 82. Kragten E, Lalande I, Zimmermann K, Roggo S, Schindler P, Mu¨ller D, Van Oostrum J, Waldmeier P, Fu¨rst 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 oxidantmediated 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 dehydrogenase 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 dopaminergic 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: discovery 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 Nallenic 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 dopamine 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 neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium. 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. Transfectionenforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase 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, Keina¨nen 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.