REDUCTION OF MPP(-INDUCED HYDROXYL RADICAL FORMATION AND NIGROSTRIATAL MPTP TOXICITY BY INHIBITING NITRIC-OXIDE SYNTHASE())

N-Methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces experime ntal parkinsonism after oxidation to N-methylpyridinium ion (MPP(+)), accumulation in dopamine neurons and concentration in mitochondria. In hibition by MPP(+) of mitochondrial electron transport impairs respira tory function, but the molecular mechanisms of cell death are not clea r. We tested the hypothesis that locally produced nitric oxide is a ke y component in MPTP toxicity by providing a necessary intermediate in the production of hydroxyl free radicals. Inhibition of nitric oxide s ynthase reduced MPP(+)-induced hydroxyl radical formation in striatum and MPTP toxicity to nigrostriatal dopamine terminals, but did not int erfere with inhibition of complex-I activity. Nitric oxide appears to be necessary for hydroxyl free radical generation in MPP(+) toxicity a nd may play a role in neuronal degeneration in Parkinson's disease.