Selegiline: current perspectives on issues related to neuroprotection and mortality.

Abstract

Selegiline (deprenyl, Eldepryl), in doses of 10 mg per day, is a selective inhibitor of monoamine oxidase type B (MAO-B) that avoids the cheese effect associated with peripheral MAO-A inhibition. [1,2] The drug was initially developed as an antidepressant agent [3] but was not found to be effective in doses that selectively inhibit MAO-B [4] and is no longer used for this indication. Based on the capacity of selegiline to potentially increase striatal dopamine by blocking the MAO-B metabolism of dopamine, [5] Birkmayer et al. [6] tested selegiline in Parkinson's disease (PD). Both this group and a number of other investigators [7-10] reported modest anti-Parkinson benefits and a reduction in motor fluctuations when selegiline was combined with levodopa. These observations formed the basis for the approved use of deprenyl in the United States. However, interest in selegiline has largely centered on the possibility that it might provide neuroprotective benefits in PD and slow the rate of disease progression. Recently, the possibility has been raised that the addition of selegiline to levodopa therapy increases the risk of early death. [11] This article will review the status of selegiline with respect to these issues and provide a basis for determining its role in the current management of PD. ### Initial hypothesis. In the early 1980s, a group of drug addicts in northern California developed a parkinsonian syndrome following exposure to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). [12] MPTP is a byproduct of the synthesis of an illegal meperidine derivative. MPTP crosses the blood-brain barrier where it is oxidized to its active metabolite 1-methyl-4-phenylpyridine (MPP+) in a reaction catalyzed by MAO-B. [13-15] MPP+ is selectively taken up by dopamine neurons and concentrated within mitochondria, where it selectively damages complex I, induces oxidative stress, and causes a parkinsonian syndrome. Inhibition of MAO-B by drugs such as selegiline …