The hippocampal lesion induced by cerebral ischemia has several excitotoxic features. Denervation of the ischemia-vulnerable pyramidal cells has a protective effect. Because most synapses are glutamatergic, administration of glutamate antagonists after ischemia also could be protective. Growing evidence now indicates that non-N-methyl-D-aspartate antagonists are more effective than N-methyl-D-aspartate antagonists in complete global ischemia. One explanation offered is that ischemia may sensitize pyramidal neurons so that "normal" postischemic synaptic activity induces lethal damage.