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 experimental parkinsonism after oxidation to N-methylpyridinium ion (MPP+), accumulation in dopamine neurons and concentration in mitochondria. Inhibition by MPP+ of mitochondrial electron transport impairs respiratory function, but the molecular mechanisms of cell death are not clear. We tested the hypothesis that locally produced nitric oxide is a key component in MPTP toxicity by providing a necessary intermediate in the production of hydroxyl free radicals. Inhibition of nitric oxide synthase reduced MPP(+)-induced hydroxyl radical formation in striatum and MPTP toxicity to nigrostriatal dopamine terminals, but did not interfere with inhibition of complex-I activity. Nitric oxide appears to be necessary for hydroxyl free radical generation in MPP+ toxicity and may play a role in neuronal degeneration in Parkinson's disease.
Smith
T S
TS
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
Swerdlow
R H
RH
Parker
W D
WD
Bennett
J P
JP
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors*; D020267:MPTP Poisoning; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase; D016548:Prosencephalon / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects*
D011726:Pyridinium Compounds; D017665:Hydroxyl Radical; C014677:1-methylpyridinium; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D016660:NAD(P)H Dehydrogenase (Quinone)