APOPTOSIS AND NECROSIS - 2 DISTINCT EVENTS INDUCED, RESPECTIVELY, BY MILD AND INTENSE INSULTS WITH N-METHYL-D-ASPARTATE OR NITRIC-OXIDE SUPEROXIDE IN CORTICAL CELL-CULTURES

N-Methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity may depend , in part, on the generation of nitric oxide (NO.) and superoxide anio n (O-2(.-)), which react to form peroxynitrite (OONO-). This form of n eurotoxicity is thought to contribute to a final common pathway of inj ury in a wide variety of acute and chronic neurologic disorders, inclu ding focal ischemia, trauma, epilepsy, Huntington disease, Alzheimer d isease, amyotrophic lateral sclerosis, AIDS dementia, and other neurod egenerative diseases. Here, we report that exposure of cortical neuron s to relatively short durations or low concentrations of NMDA, S-nitro socysteine, or 3-morpholinosydnonimine, which generate low levels of p eroxynitrite, induces a delayed form of neurotoxicity predominated by apoptotic features. Pretreatment with superoxide dismutase and catalas e to scavenge O-2(.-) partially prevents the apoptotic process trigger ed by S-nitrosocysteine or 3-morpholinosydnonimine. In contrast, inten se exposure to high concentrations of NMDA or peroxynitrite induces ne crotic cell damage characterized by acute swelling and lysis, which ca nnot be ameliorated by superoxide dismutase and catalase. Thus, depend ing on the intensity of the initial insult, NMDA or nitric oxide/super oxide can result in either apoptotic or necrotic neuronal cell damage.