Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B.
Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl 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 deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.
Finnegan
K T
KT
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City 84112.
Skratt
J J
JJ
Irwin
I
I
DeLanney
L E
LE
Langston
J W
JW
D000498:Allyl Compounds; D000818:Animals; D001596:Benzylamines / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D002082:Butylamines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology*
D000498:Allyl Compounds; D001596:Benzylamines; D002082:Butylamines; D008996:Monoamine Oxidase Inhibitors; C058000:mofegiline; D012642:Selegiline; C030796:benzylamine; C012102:DSP 4; D009638:Norepinephrine