σ-Ligands and non-competitive NMDA antagonists inhibit glutamate release during cerebral ischemia

Release of glutamate from brain cells is increased during ischemia and is thought to be involved in ischemic damage. In rat hippocampal slices the release of glutamate during ‘in vitro ischemia’ (anoxia without glucose) is shown to be blocked by two groups of compounds: non-competitive N-methyl-d-aspartate (NMDA) antagonists and sigma ligands. The effects are selective for the ischemic glutamate release, which is independent of extracellular Ca2+. High K+, Ca2+ dependent, induced release of glutamate is not inhibited. NMDA receptor blockade normally does not prevent ischemic transmission damage in the rat hippocampal slice. However, when ischemic glutamate release is attenuated, NMDA receptor antagonists do prevent the damage. This indicates that high levels of glutamate may cause damage via non-NMDA as well as NMDA receptors.