EFFECTS OF NITRIC-OXIDE SYNTHASE INHIBITION ON BRAIN INFARCTION IN SOD-1-TRANSGENIC MICE FOLLOWING TRANSIENT FOCAL CEREBRAL-ISCHEMIA

To investigate the role of superoxide in the toxicity of nitric oxide (NO), we examined the effect of nitric oxide synthase (NOS) inhibition on brain infarction in transgenic mice overexpressing CuZn-superoxide dismutase (SOD-1). Male SOD-transgenic mice and nontransgenic litterm ates (30-35 g) were subjected to 60 min of middle cerebral artery occl usion followed by 24 h of reperfusion. Either N-G-nitro-L-arginine met hyl ester (L-NAME; 3 mg/kg), a mixed neuronal and endothelial NOS inhi bitor, or 7-nitroindazole (7-NI; 25 mg/kg), a selective neuronal NOS i nhibitor, was administered intraperitoneally 5 min after the onset of ischemia. At 24 h of reperfusion, the mice were decapitated and the in farct volume was evaluated in each group. In the nontransgenic mice, L -NAME significantly increased the infarct volume as compared with the vehicle, while 7-NI significantly decreased it. In the SOD-transgenic mice, L-NAME-treated animals showed a significantly larger infarct vol ume than vehicle-treated ones, whereas there were no significant diffe rences between 7-NI- and vehicle-treated mice. Our findings suggest th at selective inhibition of neuronal NOS ameliorates ischemic brain inj ury and that both neuronal and endothelial NOS inhibition may result i n the deterioration of ischemic injury due to vasoconstriction of the brain. Since L-NAME increased infarct volume even in SOD-transgenic mi ce, the protective effect of SOD could result from the vasodilation by increased endothelial NO as well as the reduction of neuronal injury due to less production of peroxynitrite compared to wild-type mice. Mo reover, the neurotoxic role of NO might not be dependent on NO itself, but the reaction with superoxide to form peroxynitrite, because of no additive effects of SOD and a neuronal NOS inhibitor.