Glutamate released by activated microglia induces excito-neurotoxicity and may contribute to neurodegeneration in numerous neurological diseases including ischemia, inflammation, epilepsy, and neurodegenerative diseases. We observed that the gap junction blocker carbenoxolone (CBX) or the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) decreased glutamate release from activated microglia and rescued neuronal death in a dose-dependent manner in vitro. In gerbils, treatment with CBX or DON also prevented the delayed death of hippocampal neurons following transient global ischemia. Thus, blockade of microglial glutamate release may be an effective therapeutic strategy against neurodegeneration after ischemic injury.