Résumé
In cerebellar granule cells, endogenous production of NO tonically blocks N-methyl- D-aspartate (NMDA) receptors. Superoxide ions seem to be more efficient than NO at inducing NMDA neurotoxicity. Under experimental conditions, blocking NO formation did not prevent glutamate neurotoxicity in vitro or in vivo. On the contrary, complete depletion of NO synthesis increased the deleterious action of NMDA on neurons, probably by suppressing the negative feedback exerted by NO on NMDA receptors. In vitro studies showed that purified nitric oxide synthase can produce oxygenated free radicals such as superoxide ion when L-arginine concentrations are low. However, this was not the case under our experimental conditions, as indicated by the production of NO and cyclic guanosine monophosphate upon NMDA receptor stimulation, because neurons are usually not depleted in L-arginine. Moreover, under such conditions NO Arg did not suppress NMDA-induced superoxide ion production. Activation of phospholipase A2 induced by NMDA receptor stimulation may be an important although not exclusive step in the generation of oxygen radicals and neuronal death.