GLUTAMATE TRIGGERS CELL-DEATH SPECIFICALLY IN MATURE CENTRAL NEURONS THROUGH A NECROTIC PROCESS

Whereas immature neurons have been shown to be sensitive to hypoxia an d to develop apoptosis, the role of glutamate in neuronal injury is mo re controversial. Effects of a 6-h exposure to glutamate or its analog ues (100 mu M) were studied over a period of 72 h in cultured central neurons at two maturational stages, i.e., after 6 and 13 days in vitro . Glutamate was without toxic effects in 6-day-old neurons which becam e vulnerable to the excitatory amino acid when they were coexposed to 30 nM staurosporine, a protein kinase C inhibitor. In 13-day old neuro ns, glutamate and derivatives led to cell death and altered functional activity of surviving neurons over the next 72 h, the greatest injury being observed with glutamate and NMDA. At this developmental stage, persistent inhibition of protein synthesis induced by glutamate, as we ll as lack of beneficial effect from cycloheximide, argues against pro grammed neuronal death. Accordingly, quantitative cell nuclear analysi s using a fluorescent dye revealed that the effects of glutamate refle ct necrosis but not apoptosis. Furthermore, the inability of immature neurons to inhibit protein kinase C may account for their higher resis tance to excitotoxicity. (C) 1998 Academic Press.