Antagonism of NMDA receptors by σ receptor ligands attenuates chemical ischemia-induced neuronal death in vitro

We investigated the effects of σ receptor ligands on neuronal death induced by chemical ischemia using primary cultures of rat cerebral cortical neurons. The induction of chemical ischemia by sodium azide and 2-deoxy-D-glucose led to delayed neuronal death in a time- and concentration-dependent manner, as determined by trypan blue exclusion. The neurotoxicity was inhibited by N-methyl-D-aspartate (NMDA) receptor antagonists, indicating the involvement of glutamate. The σ receptor ligands (+)-N-allylnormetazocine ((+)-SKF10,047) and haloperidol, but not carbetapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP), prevented chemical ischemia-induced neurotoxicity in a concentration-dependent manner. The protective effects of (+)-SKF10,047 and haloperidol were not affected by the σ receptor antagonists. (+)-SKF10,047 and haloperidol, but not carbetapentane and (+)-3PPP, inhibited the glutamate-induced increase in intracellular Ca²⁺, and the inhibitory effects were not attenuated by σ receptor antagonists. These results suggest that direct interaction with NMDA receptors but not σ receptors is crucial to the neuroprotective effects of σ receptor ligands with affinity for NMDA receptors.