Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms.

A reduced blood or oxygen supply to the brain leads to neuronal death caused by excessive activation of glutamate receptors. Recent evidence suggests that two distinct phases of glutamate release produce this death. During ischaemia or hypoxia, glutamate is released by reversed operation of glutamate uptake carriers. It activates N-methyl-D-aspartate (NMDA) receptors, increases the intracellular concentration of Ca2+, and triggers a long-lasting potentiation of NMDA-receptor-gated currents. After ischaemia, glutamate released by Ca(2+)-dependent exocytosis activates an excessive influx of Ca2+ largely through potentiated NMDA-receptor-channels, which leads to neuronal death. The therapeutic implications of such a scheme are discussed.