A DUAL ROLE FOR NITRIC-OXIDE IN NMDA-MEDIATED TOXICITY IN-VIVO

Nitric oxide has been implicated in N-methyl-D-aspartate (NMDA)-mediat ed damage in vitro however, its role in excitotoxic damage in vivo is not clear, In the present study we evaluated the histopathological and hemodynamic consequences of intrastriatal injections of various doses of NMDA and determined the effects of nitric oxide synthase inhibitio n on these changes, NMDA was injected into the striatum at doses of 50 , 150, and 300 nmol with or without N-omega-nitro-L-arginine methyl es ter (L-NAME; 100 mu g, locally), Three days following injections histo pathological assessment was performed by morphometric analysis of the lesion area in multiple sections taken from the anterior to the poster ior borders of the lesion. In animals injected with 150 and 300 nmol o f NMDA (+/-L-NAME), local CBF (ICBF) was determined 30 min following i njections using C-14-iodoantipyrine autoradiography. All NMDA-treated animals showed a well-demarcated lesion extending beyond the injection site. The volume of the lesion correlated significantly with the NMDA dose injected. The effects of L-NAME on lesion size were dependent on the dose of the NMDA. The lesion induced by 50 nmol of NMDA was not a ffected by L-NAME. With a dose of 150 nmol of NMDA, L-NAME induced a 4 3% increase in lesion volume, In contrast, a 38% decrease in lesion si ze was observed in animals treated with 300 nmol of NMDA combined with L-NAME, At a dose of 150 nmol, NMDA induced a significant elevation i n ICBF, which was restricted to regions close to the injection site in cluding the center areas of the anterior and middle striatum, The incr ease in ICBF observed with 150 nmol of NMDA was significantly attenuat ed in the NMDA + L-NAME-treated group. The ICBF changes induced by 300 nmol. of NMDA were not significantly different from those in the 150- nmol group; however, the extent of the regions involved was larger. Th e increases in ICBF were observed in all striatal regions including th e central and peripheral areas. L-NAME did not have a significant effe ct on the ICBF changes induced by NMDA at a dose of 300 nmol. These da ta suggest that in vivo the involvement of nitric oxide in NMDA toxici ty depends on the NMDA dose and on the participation of hemodynamic me chanisms secondary to NMDA exposure.