Inhibition of nitric oxide synthase activity attenuates striatal malonate lesions in rats.
Mitochondrial inhibitors such as malonate are potent neurotoxins in vivo. Intrastriatal injections of malonate result in neuronal damage reminiscent of "excitotoxic" lesions produced by compounds that activate NMDA receptors. Although the mechanism of cell death produced by malonate is uncertain, overactivation of NMDA receptors may be involved; pretreatment of animals with NMDA antagonists provides neuroprotection against malonate lesions. NMDA receptor activation stimulates the enzyme nitric oxide (NO) synthase (NOS). Elevated tissue levels of NO may generate highly reactive intermediates that impair mitochondrial function. We hypothesized that NO may be a mediator of malonate toxicity. We investigated whether in vivo inhibition of NO production by the NOS inhibitor N omega-nitro-L-arginine (NLA) would attenuate lesions produced by intrastriatal injections of malonate. We found that systemic injections of 3 mg/kg of NLA significantly reduced the extent of histologic damage elicited by intrastriatal injections of 1.5 mumol of malonate in adult rats.
Maragos
W F
WF
Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109-0646, USA.
Silverstein
F S
FS
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D008314:Malonates; D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D001120:Arginine; C030290:malonic acid; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D003576:Electron Transport Complex IV