Antioxidative Therapeutic Strategies for Parkinson's Disease" IRA SHOULSON Dq~rtmena of NeuloroBy and PhamracOroBy Untimiq of Rochesrer Medkal Center Rochester, New Ymk 14642

The pathogenesis of nigral degeneration underlying Parkinson's disease (PD) has been linked to neurotoxic mechanisms involving oxidation-mediated events.' Deamination of dopamine by age-related increases in monoamine oxidase (MAO) may result in increased fbrmation of hydrogen peroxide and other potentially toxic bypmducts. Depletion of free-radical scavenger enzymes, increased oxidized iron, and heightened lipid peroxidation predispose further to the intrinsic vulnerabilities underlying nigral degeneration. Environmental factors may prompt or hasten nigral degeneration through actions of protoxins, such as l-methyl-Q-phenyl-l,2,5,6-tetrahydmpyridine (MPTP), whose toxicity depends on the oxidative biotransfbrmation.

CLINICAL AND PHARMACOLOGIC CONSIDERATIONS Parkinson's disease is a slowly advancing neumdegenerative disorder which results largely from progressive dysfunctionand death ofneurons within the nigrostriataldopamine pathway. Clinical features of tremor, rigidity, bradykinesia and postural instability emerge gradually after depletion of 70% to 90%of the pigmented neurons in the pars compacta of the substantia n i p . A variety of aging, environmental, and genetic risk factors have been proposed to account for nigral vulnerability.lJ At present, there are no reliable means of detecting normal-appearing persons who are at increased risk to develop PD.3 In the past two decades, dopamine replacement therapies have been developed to treat the symptoms of PD. These therapies derive their benefit lacgely from restoration of depleted nigrostriatal dopamine (e.g., by levodopa) or stimulation of dopamine receptors (e.g., by bromocriptine or pergolide). However, dopaminergic therapies are often attended by adverse motor and mental effects in the setting of slowly progressive clinical deterioration. ~Deprenylor seleghne is a phenethylamine derivative which irreversibly inhibits MA0 type B (MAO-B) when administered in humans at a daily dosage of 10 mg.4 Deprenyl may enhance nigrosviatal dopamine by inhibition of dopamine catabohsm and interference with presynaptic reuptake of dopamine. Approximately 85-95% of MAO-B is depleted in the postmortem brain of deprenyl-treated PD patients.5 a The DNATOP study was supported primarily by USPHS Grant NS 24778 from the National Institutes of Health.

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ANNALS NEW YORK ACADEMY OF SCIENCES

cDeprenyl is metabolized to Gamphetamine and cmethamphetamine, which have mean half-lives, respectively, of 17.7 hours and 17.5 hours. L-Amphetamine and tmethamphetamine interfere with neuronal uptake and enhance release of endogenous catecholamines, but these pharmacologic properties appear to be less clinically relevant than the effects of ~isomers.6~7 In mice, deprenyl suppresses the oxidant stress associated with increased dopamine turnover as measured by the accumulation of glutathione disuUide.* In 1985, Birkmayer and colleagues9 reported increased life expectancy in moderately advanced PD patients who were treated with deprenyl in combination with levodopa as compared with patients who were treated with levodopa alone. This uncontrolled, retrospective analysis attributed the beneficial effects of deprenyl to its MAO-B-inhibiting properties. In otherwise untreated patients with early PD, the short-term symptomatic benefits of deprenyl have been reported to be modest or neghgible. Alpha-tocopherol is an antioxidant that exerts free-radical scavenger activity by inhibition of oxidation of unsaturated Eatty acids.15 On the basis of these properties and the presumed oxidative stress contributing to nigral degeneration, Fahn16 treated 12 early PD patients with vitamin E in dosages of up to 3,000 IU daily. In this uncontrolled investigation, 2.5 years to 7.5 years of benefit were observed in vitamin E-treated patients before dopaminetgic therapy was needed to treat supervening disability.

CONTROLLED CLINICAL TRIAL OF DEPRENYL IN EARLY PD To the extent that MA0 activity and the formation of oxygen radicals contribute to the pathogenesis of nigral degeneration, deprenyl, tocopherol, or both may be expected to slow the clinical progression of PD. The trial “Deprenyland Tocopherol Anti-

oxidative Therapy of Parkinsonism” (DAllTOP) is based on the hypothesis that deprenyl and/or tocopherol extend the interval before sufficiently severe disability from PD prompts the initiation of levodopa therapy in patients with early illness. This placebocontrolled, double-blind, multicenter clinical trial recruited 800 subjects with early, otherwise untreated PD who were randomly assigned by a 2 x 2 fictorial design to one of four treatment groups: deprenyl(l0 mg/day) and tocopherol placebo; deprenyl placebo and tocopherol (2000 IU/day); deprenyl (10 mg/day) and tocopherol (2000 IU/day); or deprenyl placebo and tocopherol placebo. A stratified mdomization helped to ensure that each of the 34 participating DATATOP investigators were assigned an approximate numerical balance of subjects in each of the four treatment groups. Subjects were reevaluated after baseline evaluation at 1 month and 3 months and then at approximately 3-month intervals with respect to a variety of standardized clinical measures relevant to PD. The primary end-point of the trial occurred when, in the judgment of the enrolling investigator, the subject reached a level of functional disability sufficient to warrant the initiation of levodopa therapy. Prompted by the recommendations of an independent monitoring committee, preliminary data analysis was carried out after 12 f 5 months of follow-up evaluation comparing the 401 subjects not receiving deprenyl with the 399 subjects receiving de-

S H O W N : ANTIOXIDATIVE THERAPEUTIC SI’RATEGIES

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prenyl, regardless of their tocopherol assignment^.'^ The limited and preliminary analysis disclosed that 176 subjects in the non-deprenyl treatment group had reached the end-point of disability while only 97 subjects in the deprenyl treatment group had reached this end-point (p < In suMval terms, a 57% reduction in the risk of reaching the end-point was observed for subjects assigned to deprenyl compared with subjects not assigned to deprenyl (p < 10-lo). Of the 392 subjects who were fully employed at entry into the study, an approximate 50% reduction in the risk of ceasing full-time employment was fbund favoring subjects assigned to deprenyl treatment ( p = 0.01).Only a modest 10% amelioration of PD features was observed as a consequence of deprenyl treatment. In a similarly designed study involving 51 PD subjects, Tetrud and Langstonls reported results strikingly similar to the preliminary DAUlDP findings, demonstrating that deprenyl produced a clear and statistically significant delay in the time until levodopa therapy was required (p < 0.002). In their study, which fbllowed subjects 6 r a maximum of 3 years, no statistically significant symptomatic benefits of deprenyl therapy on PD motor signs were observed. Other smaller trials have detected modest or neghgible amelioration of PD features owing to deprenyl, on the order of 0% to 10% change.13.14

INTERPRETATION OF DEPWNYL TRIALS Although the effect of deprenyl in delaying the onset of a predetermined level of disability was strong and unequivocal, the benefits of deprenyl may have been due to subtle and cumulative symptomatic effects rather than genuine neuroprotection. Shortterm anti-PD effects could have resulted from increase in the availabilityof nigrostriatal dopamine through inhibition of catabolism or presynaptic reuptake of dopamine, or through similar actions related to the effects of Gmethamphetamine and camphetamine. However, such short-term anti-PD effects do not adequately explain the longterm reduction in the rate of reaching the time-related end-point of disability. When the DATATOP subjects in each treatment group were subdivided into those who initially showed improvement in motor perfbrrnance and those who initially showed a decline or no change, the difference in the rate of reaching the end-point favoring those taking deprenyl remained strong and statistically si@cant within subgroupings.17 The DATATOP protocol has been modified while maintaining the blindness of original treatment assignments. All active research subjects have been withdrawn fbr 2 months from originally assigned treatments and then followed fbr an additional 18 months on active deprenyl. The extended trial is expected to provide clues re@g the mechanism of deprenyl’s effect in early PD. Data will be analyzed after an additional 18 months of fbllow-up to compare subjects previously receiving deprenyl (for an average of 36 months) with those who were more recently started on deprenyl ( b r a n average of 18 months). If deprenyl largely exerts a symptomatic effect, then a “catch-up” in the beneficial effect on the primary end-point of disability should be demonstrated in subjects who were most recently started on active treatment. If deprenyl largely exerts a protective effect, then subjects who were previously treated with active medication should continue to maintain their benefits in comparison with subjects who were recently started on deprenyl. Data will also be analyzed regarding the independent and interactive effects of tocopherol.

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OTHER ANTINEUROTOXIC STRATEGIES Recent evidence in experimental models has suggested that the N-methyl-waspartate (NMDA)receptor may represent a final common pathway of neuronal dysfunction and death in a variety of neurologic disorders, including PD.19 NMDA antagonists, such as MK-801 and Am, can confer protection +st MPP+ (1-methyl-4-phenylpyridinium) microinjected into the rat substantia Drugs such as NBQX (dihydroxy-6-nitro-7-suffimoy-benz(f)quinoxaline),which block the AMPA (alphaamino-3-hydroxy-5-methyl4-isoxamleproprionate) subtype of glutamate receptor, exert short-term symptomatic benefits in monkeys in whom lesions had been created with MPTP.21 NMDA and AMPA antagonists warrant investigation as both symp tomatic and protective interventions in PD.

FUTURE OF ANTIOXIDATIVE STRATEGIES The success of antioxidative interventions in slowing the progression of PD depends on the refinement and expansion of clinical trials as well as on a better understanding of pathogenesis. The search continues fbr more selective and effective inhibitors of MAO-B. R019-6327,a highly selective and reversible MAO-B inhibitor that is not metabolized to active derivatives, such as amphetamines,22is currently under investigation in patients with early PD. The ultimate value of protective strategies will depend upon the demonstrated ability of these interventions to slow or prevent nlgral degeneration in humans. To achieve effective neuroprotection in PD, improved biologic markers of disease will be needed to characterize both symptomatic patients and asymptomatic individuals predisposed to nigral degeneration. Once developed and validated, these markers can be applied to clinical trials to postpone or prevent the onset of Parkinson’s disease. REPERENCES 1. PARKP~SON STUDY GROUP.1989. Dp;cpiMP: A multi-center controtled clinical tnal in early Parkinson’s disease. Arch. Neurol. 46: 1052-1060. 2. TANNER, C. M. 1989. The role of environmental Factors in the etiology of Parkinson’s disease. Trends Neuroxi. 12: 49-54. 3. LANGSTON,J. W. & W. C. KOLLER.1991. The next frontier in Parkinson’s disease: Pmymptomatic detection. Neurology 4l(Supp1.2): 5-7. 4. CHRISP, P.,G. J. MAMMEN& E. M. SOBKIN.1991. scle&ne: A review of its pharmacological properties, and symptomatic and protective therapeutic use in Parkinson’s disease. DN&Fand Aging l(3): 228-248. 5. RIEDEWA, P. & M. B. H. YOUDIM. 1986. Monoamine oxidase activity and rnonoaminc metabolism in brains of parkinsonian patients treated with cdeprenyl. J. Neurochem. 46: 1359-1365. 6. PARKBS,J. D., D. TARSY & C. D. MARSDEN, ctal. 1975. Amphetamines in the trratment of Parkinson’s disease. J. Neurol. Neurosug. Psychiat. 38: 232-237. 7. STERN,G. M.,A. J. LEES, R HARDIB, ct al. 1983. Clinical and pharmacological aspects of (-)deprenyl tmtment in Parkinson’s disease. Mod. Probl. Pharmacopsychiatcy 1 9 215-219. 8. &HEN, G. & M. B. SPINA.1989. Deprenyl suppressts the oxidant suess associated with increased dopamine turnover. Ann. Neurol. 26: 689690. 9. BIRKMAYER,W., J. KNOLL & P. RIEDERER,ctal. 1985. Increased lifc expectancy resulting

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from addition of Ldeprenyl to MadopaP treatment in Parkinson’s disease: A longterm study. J. Neural h s m . 6k 113-127. CSANDRA, E. & M.TARCZY. 1987. Scleghne in the early and later phases of Parkinson’s disease. J. Neural Tiansm. (Suppl.) 25: 105-113. EISLER, T., H. TERAVAINEN, R NELSON,ctd. 1981. Deprenyl in Parkinson disease. Neurology 31: 19-23. ELIZAN,T. S.,M. D. YAHR, D. A. M o m , ctd. 1989. Scleghne use to prcvent progression of Parkinson’s disease. Arch. Neurol. 46: 1275-1279. MYLLYW, V. V., K.A. SOTANIBMI, J. TOUMINEN, ct d.1989. Scleghne as primary theiapy in early phase Parkinson’s disease-an interim report. Acta Neurol. Scand. 126:177-182. TERAVAINEN, H. 1990. Scleg&ne in Parkinson’s disease. Acta Neurol. Scand. 81: 333-336. WILLSON,R L. 1983. Free radical protection: Why vitamin E, not vitamin C, beta-carotene or glutathione? In Biology of Vitamin E: Ciba Foundation Symposium 101. R. Porter and J. Whelan, Eds.: 19-44. Pitman Books Ltd. London. FAHN,S. 1989. The endogenous toxin hypothesis of the etiology of Parkinson’s disease and a pilot trial of hlgh-dosagc antioxidants in an attempt to slow the progression of illness. Ann. N.Y. Acad. Sci. 570: 186-1%. PARKINSON STUDYGROUP.1989. M c t of deprenyl on the progression of disability in early Parkinson’s disease. N. Engl. J. Med. 321: 1364-1371. Tmm, J. W. & J. W. LANGSTON.1989. The eEct of deprenyl (selegihne) on the natural history of Parkinson’s disease. Science 245: 519-522. GREENAMYRE, J. T. & C. F. O’BRIEN. KMethyl-waspartate antagonists in the treatment of Parkinson’s disease. Arch. Neurol. 48: 977-981. TURSKI, L., K. BRESSLER, K . J . RETIIG, P.-A. LOSCHMANN& H. WACHTEL.1991. Protection of substantia n i p from MPP+ neurotoxicity by N-methyh-aspartate a n t a p nists. Nature 31: 414-418. KLOCKG~XHER,T.,L. TURSKI, T. HONORE, Z. ZHANG,D. M. GASH, R KURLAN& J. T. GREENAMYRE. 1991. The AMPA receptor antagonist NBQX has antiparkinsonian e&cts in monoamine-depleted rats and MPTP-treated monkeys. Ann. Neurol. 30: 717-723. HOLFOPD, N. H. G., T. W. GLIENTERT, J. DINGEMANSE & R KBITLER.1991. Fully parametric and semi-parametricestimates of the pharmacodynamics of a selective monoamine oxidase B inhibitor [abstract]. Clin. Pharmacol. Ther. 49(2): 152.

Antioxidative therapeutic strategies for Parkinson's disease.

Antioxidative Therapeutic Strategies for Parkinson's Disease" IRA SHOULSON Dq~rtmena of NeuloroBy and PhamracOroBy Untimiq of Rochesrer Medkal Center...
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