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From the Division of Clinical Neurochemistry, University Hospital for Psychiatry, University of Wurzburg (Drs. Gerlach and Riederer); and the Department of Pharmacology, Faculty of Medicine, Technion, Haifa, Israel (Dr. Youdim).
Supported by grants from the Bundesministerium fur Forschung und Technologie (01 KL 9013; 01 KL 9101-0) (Drs. Gerlach and Riederer); and Golding Parkinson Disease Research Fund Technion, Haifa (Dr. Youdim). The support of the European Community in Brussels (Biomed I) and Fogarty International Center for Advanced Studies, NIH Bethesda, is gratefully acknowledged.
Address correspondence and reprint requests to Dr. Riederer, Psychiatrische Klinik und Poliklinik, Klinische Neurochemie, Fuchsleinstr. 15, D-97080 Wurzburg, Germany.
Abstract.
The acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor selegiline (previously called L-deprenyl) has proved to be a useful adjuvant to levodopa therapy and monotherapy of Parkinson's disease (PD). Selegiline is readily absorbed from the gastrointestinal tract and rapidly enters the brain and spinal cord following oral administration. The drug binds to brain regions with a high MAO-B content, such as the thalamus, the striatum, the cortex, and the brainstem. It is extensively metabolized in humans, mainly in the liver, to form desmethylselegiline and methamphetamine, which are further metabolized to amphetamine. Eighty-six percent of the 10-mg dose was recovered in the urine within 24 hours. These data suggest that accumulation of metabolites does not occur. Although not all features of its anti-PD action are known, studies using brain obtained at autopsy from patients who had been treated with 10 mg of selegiline showed that selective inhibition of MAO-B, with the concomitant increase of phenylethylamine and dopamine (DA) but not of serotonin or noradrenaline, in the basal ganglia may be regarded as its mode of action. The protective effects afforded by selegiline in PD, resulting in a delayed need for levodopa therapy, have been variously interpreted in terms of the involvement of an endogenous neurotoxin or an oxygen free radical mechanism (oxidative stress) in the development of PD. However, although many different hypotheses have been advanced and recent findings have emphasized the significance of oxidative stress in the pathogenesis of the disease, the cause of chronic nigral cell death and the underlying mechanisms remain, as yet, elusive. Therefore, there is no clear knowledge regarding an understanding of the reported effects of selegiline on the progression of PD. Nevertheless, selegiline might be expected to have some protective effects in reducing the production of potentially neurotoxic compounds resulting in the MAO-catalyzed oxidation of DA. In addition, some evidence suggests both an indirect (via induction of radical-scavenging enzymes) and a direct antioxidant function for selegiline. On the other hand, the reported protective effect of selegiline might also receive a contribution from the diminished potentiation of the N-methyl-D-aspartate receptor by the polyamine binding site. Finally, the effects of selegiline might also involve preventing, or perhaps to some extent reversing, the decline in resistance normally associated with cellular aging because of its neurotrophine-like action. However, even in the early clinical stage of PD, the sequence of events leading to nigral cell death may be too far advanced for selegiline to exhibit its maximum potential.
NEUROLOGY 1996;47(Suppl 3): S137-S145
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