Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?

Summary Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists (competitive receptor antagonists, ion channel blockers, and glycine antagonists)—such as selfotel, aptiganel, eliprodil, licostinel and gavestinel—failed to show efficacy in clinical trials of stroke or traumatic brain injury. This failure has been attributed to the deficient properties of the molecules that entered human trials and to inappropriate design of clinical studies. In this article we hypothesise that glutamate may be involved in the acute neurodestructive phase that occurs immediately after traumatic or ischaemic injury (excitotoxicity), but that, after this period, it assumes its normal physiological functions, which include promotion of neuronal survival. We propose that NMDA receptor antagonists failed stroke and traumatic brain injury trials in human beings because blockade of synaptic transmission mediated by NMDA receptors hinders neuronal survival.