INHIBITION OF NITRIC-OXIDE SYNTHASE ACTIVITY ATTENUATES STRIATAL MALONATE LESIONS IN RATS

Mitochondrial inhibitors such as malonate are potent neurotoxins in vi vo. Intrastriatal injections of malonate result in neuronal damage rem iniscent of ''excitotoxic'' lesions produced by compounds that activat e NMDA receptors. Although the mechanism of cell death produced by mal onate 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 enz yme nitric oxide (NO) synthase (NOS). Elevated tissue levels of NO may generate highly reactive intermediates that impair mitochondrial func tion. 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-w-nitro-L-arginine (NLA) would attenuate lesions produced by intrastriatal injections of malonate. We round that systemic injec tions of 3 mg/kg of NLA significantly reduced the extent of histologic damage elicited by intrastriatal injections of 1.5 mu mol of malonate in adult rats.