Reduction of MPP(+)-induced hydroxyl radical formation and nigrostriatal MPTP toxicity by inhibiting nitric oxide synthase

Neuroreport. 1994 Dec 20;5(18):2598-600. doi: 10.1097/00001756-199412000-00048.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Oxidoreductases / antagonists & inhibitors*
  • Animals
  • Corpus Striatum / drug effects*
  • Hydroxyl Radical / antagonists & inhibitors*
  • MPTP Poisoning*
  • Male
  • Mitochondria / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / antagonists & inhibitors
  • Nitric Oxide Synthase
  • Prosencephalon / metabolism
  • Pyridinium Compounds / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Substantia Nigra / drug effects*

Substances

  • Pyridinium Compounds
  • Hydroxyl Radical
  • 1-methylpyridinium
  • Nitric Oxide Synthase
  • Amino Acid Oxidoreductases
  • NAD(P)H Dehydrogenase (Quinone)