Neurotoxins and monoamine oxidase inhibition: new aspects.
Recent clinical studies suggest that selegiline (L-deprenyl) is useful in retarding the progress of Parkinson's disease, an effect that may be related to its inhibition of monoamine oxidase type B (MAO-B). Selegiline is also reported to prevent the toxic effects of the noradrenergic neurotoxin, N-(2-chloroethyl)-N-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 C57Bl/6 mice were given DSP-4 (50 mg/kg) 1 h, 24 h, or 4 days after the administration of selegiline (10 mg/kg) or the selective MAO-B inhibitor MDL 72974 (1.25 mg/kg) and then killed 1 week later for the assay of norepinephrine in the hippocampus. The MAO-B-inhibiting effects of selegiline or MDL 72974 were also determined after these same intervals. Selegiline and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (> 95%), 24 h (> 90%), or 4 days (> 70%) after their administration. Given 1 h before, selegiline totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 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 selegiline to protect against DSP-4-induced neuronal degeneration does not depend on its inhibition of MAO-B.
Finnegan
K T
KT
Department of Psychiatry, University of Utah School of Medicine.
D000818:Animals; D001596:Benzylamines / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008995:Monoamine Oxidase / Q000502:physiology*; D009410:Nerve Degeneration / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins; D009638:Norepinephrine / Q000502:physiology; D012642:Selegiline / Q000494:pharmacology*
D001596:Benzylamines; D007527:Isoenzymes; D009498:Neurotoxins; D012642:Selegiline; D008995:Monoamine Oxidase; C012102:DSP 4; D009638:Norepinephrine