ATTENUATION OF MALONATE-INDUCED DEGENERATION OF THE NIGROSTRIATAL PATHWAY BY INHIBITORS OF NITRIC-OXIDE SYNTHASE

Focal infusions of the succinate dehydrogenase inhibitor, malonate, in to the substantia nigra pars compacta (SNc) of adult Sprague-Dawley ra ts resulted in a substantial depletion of ipsilateral striatal tyrosin e hydroxylase (TH) activity. The percentage decrease in striatal TH ac tivity following intranigral malonate (0.5 mu mol/0.5 mu l) infusion w as similar at 4 (58%) and 7 days (62%) post-infusion. To assess the ro le of N-methyl-D-aspartate (NMDA) receptor activation in malonate neur otoxicity, animals were pretreated with the NMDA receptor antagonist M K-801 (2 x 5 mg/kg, i.p.). Four days post-infusion of malonate (0.5 mu mol/0.5 mu l) into the SNc, striatal TH activity was depleted by 58% in vehicle pretreated animals and 14% in the presence of MK-801 indica ting a significant neuroprotective effect of MK-801 on malonate action . To determine the role of nitric oxide (NO) in malonate-induced nigra l toxicity, the actions of malonate were evaluated in the presence of the nitric oxide synthase (NOS) inhibitors, 7-nitro indazole (7-NI) an d N-omega-nitro-L-arginine methyl ester (L-NAME). Systemic injections of 7-NI (20, 30, 40, 50 and 75 mg/kg, i.p.) produced a dose-related in hibition of nigral NOS activity which was maximal at a dose of 40 mg/k g. Intranigral infusion of malonate with 20 and 50 mg/kg 7-NI pretreat ment produced a 46 and 31% decrease in striatal TH activity, respectiv ely. Thus, a significant protective effect at the higher but not lower dose of 7-NI was observed. Pretreatment with a L-NAME regimen (2 x 25 0 mg/kg; i.p.), previously shown to inhibit brain NOS activity by grea ter than 86%, also produced a significant neuroprotective effect again st malonate-induced neurotoxicity (30% decrease). The results of this study suggest that malonate-induced toxicity to the dopaminergic neuro ns of the nigrostriatal pathway is mediated, at least in part, by NMDA receptor activation and the formation of NO. (C) 1996 Elsevier Scienc e Ltd.