Recent clinical studies suggest that selegiline (1.-deprenyl) is useful in retarding the progress of Parkinson's disease. an effect that may bc related to its inhibition of monoamine oxidase type B (MAO-B). Selegilinc is also reported to prevent the toxic effects of the norddrenergic neurotoxin, h~-(2-chloroethyl)-.~--ethyl-2-bromobenzylamine (DSP-4). This article reviews recent studies on the role of MAO-B and its inhibition in this neuroprotective action of selegiline. Male C57BI/ 6 mice were given DSP-4 (50 mg/kg) 1 h, 24 h, or 4 days after the administration of selegiline (I0 mg/kg) or the selective MAO-B inhibitor MDL 72974 ( 1.25 nig/ kg) and then killed 1 week later for the assay of norepinephrine in the hippocampus. The MAO-B-inhibiting effects o f sclegiline or MDL 72974 were also detcrmined after these same intervals. Selegiline and MDL 72974 produced comparable degrees of enzyme inhibition I h (>95%), 24 h (>90%), or 4 days (>70%) after their administration. Given 1 h before, selegiline totally blocked the norepinephrinedepleting effects of DSP-4, but this protection declined sharply when 24 h o r 4 days was allowed to elapse between selegiline and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, no activity was observed when DSP-4 was used as a substrate for MAO. All of these findings suggest that the ability of sclegiline to protect against DSP-4-induced neuronal degeneration does not depend on its inhibition o f MAO-B.