Tissue responses to ischemia influx into neurons. The gating of glutamate receptor–activated channels effectively achieves membrane shunting, which spreads in waves (spreading depression) from the ischemic core out toward the margins of the ischemic zone (ischemic penumbra). Spreading depression increases metabolic demand and energy failure, thus further enhancing glutamate release. Marked neuronal cell body swelling and dendrite swelling occur, hallmarks of necrosis death, as Na+ and Ca2+ entry is joined by the influx of Cl–and water. Elevations in neuronal intracellular free Ca2+([Ca2+] i), mediated both directly by NMDA receptors and indirectly via membrane depolarization–activated voltagegated Ca2+ channels and reverse operation of the Na+-Ca2+ exchanger, bear particular responsibility for promoting spreading depression and triggering deleterious cytotoxic cascades. In neuronal cell cultures, selective NMDA receptor blockade prevents most of the Ca2+ influx and cell death induced by brief intense glutamate exposures (1). NMDA antagonists also markedly attenuated the death of cultured neurons induced by oxygen and/or glucose deprivation, observations that fit well with studies conducted with selective agonists. Exposure to NMDA for as little as 3–5 minutes is sufficient to trigger widespread cultured cortical neuronal death (“rapidly triggered excitotoxicity”), whereas exposure to even saturating concentrations of kainate typically requires hours to do the same (“slowly triggered excitotoxicity”). This difference in time course fits with a higher rate of Ca2+ influx mediated directly by NMDA receptor–gated channels, compared with a slower rate of Ca2+ influx mediated by the voltage-gated channel and exchanger routes activated by AMPA or kainate receptors. NMDA receptor antagonists are also highly neuroprotective in animal models of focal brain ischemia, as well as hypoglycemia or trauma (2), although not transient global ischemia (3). In this latter setting, NMDA receptor–mediated excitotoxicity may be less prominent than AMPA receptor–facilitated Zn2+ entry in inducing lethal neuronal injury (see below). Reasons for this shift in prominence are presently not welldefined, but a contributing factor may be extracellular acidity due to accumulation of lactic acid during global ischemia, an event less prominent in the penumbra of focal ischemia where perfusion is partially maintained. This acid shift selectively downregulates NMDA receptors and NMDA receptor–mediated excitotoxicity but enhances AMPA receptor–mediated excitotoxicity (4); it may also enhance toxic Zn2+ entry through voltage-gated Ca2+ channels (5).