Increase in external glutamate and NMDA receptor activation contribute to H2O2-induced neuronal apoptosis

The present study aims to investigate the role of extracellular glutamate a nd NMDA receptor stimulation in the neuronal death induced by a transient e xposure to H2O2 of cultured neurons originating from mouse cerebral cortex. Most of the neuronal loss following a transient exposure to H2O2 of cortic al neurons results from an apoptotic process involving a secondary stimulat ion of NMDA receptors, which occurs after H2O2 washout. Indeed, (a) the neu rotoxic effect of H2O2 was strongly reduced by antagonists of NMDA receptor s, (b) the neurotoxic effect of H2O2 was enhanced in the absence of Mg2+, ( c) the protective effect of MK-801 progressively decayed when it was applie d with increasing delay time after H2O2 exposure, and (d), finally, the ext racellular concentration of glutamate was increased after H2O2 exposure. Th e major part of H2O2-induced neurotoxicity is mediated by the formation of hydroxyl radicals, which might be involved in (a) the delayed accumulation of extracellular glutamate acid NMDA receptor activation and (b) the poly(A DP-ribose) polymerase activation and the related NAD content decrease. The combination of these two mechanisms could lead to both an increase in ATP c onsumption and a decrease of ATP synthesis. The resulting large decrease in ATP content might be finally responsible for the neuronal death.