PHARMACOLOGY OF SELEGILINE

The acetylenic selective monoamine oxidase (MAO) type B suicide inhibi tor selegiline (previously called L-deprenyl) has proved to be a usefu l adjuvant to levodopa therapy and monotherapy of Parkinson's disease (PD). Selegiline is readily absorbed from the gastrointestinal tract a nd rapidly enters the brain and spinal cord following oral administrat ion. The drug binds to brain regions with a high MAO-B content, such a s the thalamus, the striatum, the cortex, and the brainstem. It is ext ensively metabolized in humans, mainly in the liver, to form desmethyl selegiline and methamphetamine, which are further metabolized to amphe tamine. Eighty-six percent of the 10-mg dose was recovered in the urin e within 24 hours. These data suggest that accumulation of metabolites does not occur. Although not all features of its anti-PD action are k nown, studies using brain obtained at autopsy from patients who had be en treated with 10 mg of selegiline showed that selective inhibition o f MAO-B, with the concomitant increase of phenylethylamine and dopamin e (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, h ave been variously interpreted in terms of the involvement of an endog enous neurotoxin or an oxygen free radical mechanism (oxidative stress ) in the development of PD. However, although many different hypothese s have been advanced and recent findings have emphasized the significa nce 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 unde rstanding 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 compound s resulting in the MAO-catalyzed oxidation of DA. In addition, some ev idence suggests both an indirect (via induction of radical-scavenging enzymes) and a direct antioxidant function for selegiline. On the othe r hand, the reported protective effect of selegiline might also receiv e a contribution from the diminished potentiation of the N-methyl-D-as partate receptor by the polyamine binding site. Finally, the effects o f 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 c ell death may be too far advanced for selegiline to exhibit its maximu m potential.