Suppression of hydroxyl radical formation by MAO inhibitors: a novel possible neuroprotective mechanism in dopaminergic neurotoxicity.
Prior studies concluded that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a toxin causing parkinsonism) and its analogues are bioactivated by monoamine oxidase (MAO) to toxic pyridinium metabolites. Recently, a dissociation between the neuroprotective effects of deprenyl and its MAO inhibiting effects has been proposed. Furthermore, we have demonstrated that pyridinium metabolites of MPTP stimulate dopamine efflux and the formation of cytotoxic hydroxyl free radicals (.OH) in the striatum. Therefore, we investigated possible neuroprotective mechanisms of propargyl MAO inhibitors by studying their effects on the formation of oxygen free radicals produced by dopamine autoxidation. Our recent in vivo results indicate that deprenyl and clorgyline given systemically suppressed the generation of .OH that followed administration of 2'-methyl-MPTP. Combined deprenyl and clorgyline pretreatment are needed to block dopamine neurotoxicity elicited by 2'-methyl-MPTP. The present in vitro studies reveal that propargyl MAO inhibitors suppress non-enzymatic dopamine autoxidation and associated free radical production. Thus, .OH generation evoked by MPTP analogues may be due mainly to a burst increase in iron-catalyzed autoxidation of released dopamine in the basal ganglia where high levels of iron and oxygen are present. Our present in vitro and prior in vivo results suggest that a novel antioxidant property of propargyl MAO inhibitors may contribute to protection against nigral lesions elicited by dopamine autoxidation following the administration of MPTP analogues.
Chiueh
C C
CC
Laboratory of Clinical Science, National Institute of Mental Health, NIH, Bethesda, Maryland.
Huang
S J
SJ
Murphy
D L
DL
D001205:Ascorbic Acid / Q000494:pharmacology; D003010:Clorgyline / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors*; D008543:Melanins / Q000096:biosynthesis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009420:Nervous System / Q000187:drug effects*; D010084:Oxidation-Reduction / Q000187:drug effects; D010293:Pargyline / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D008543:Melanins; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D017665:Hydroxyl Radical; D010293:Pargyline; D003010:Clorgyline; D001205:Ascorbic Acid; D004298:Dopamine