Delayed neuronal death induced by transient forebrain ischemia in the rat hippocampus is preceded by a prominent microglial reaction which begins within minutes after the ischemic injury. In the present study we have examined the effect of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on microglial activation and neuronal survival. Using lectin histochemistry to detect microglia, we show that the systemic administration of MK-801 prior to ischemia prevents microglial activation, as well as delayed death of CA1 pyramidal neurons. The results demonstrate that early blockage of the glutamate cascade prevents microglial activation, and could suggest a role for microglia in mediating ischemic injury.