NMDA Antagonist Neurotoxicity: Mechanism and Prevention

Drugs that block NMDA glutamate receptors, such as PCP and ketamine, protect the brain from damage in conditions like stroke, but they also cause psychotic-like symptoms in humans and damage neurons in the rat cerebral cortex. This damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act on GABA receptors and also suppress the psychotic symptoms caused by ketamine. These findings suggest it may be possible to block the unwanted side effects of NMDA antagonists, making them more useful as neuroprotective treatments.

Study at a glance

Abstract

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, including phencyclidine (PCP) and ketamine, protect against brain damage in neurological disorders such as stroke. However, these agents have psychotomimetic properties in humans and morphologically damage neurons in the cerebral cortex of rats. It is now shown that the morphological damage can be prevented by certain anticholinergic drugs or by diazepam and barbiturates, which act at the gamma-aminobutyric acid (GABA) receptor-channel complex and are known to suppress the psychotomimetic symptoms caused by ketamine. Thus, it may be possible to prevent the unwanted side effects of NMDA antagonists, thereby enhancing their utility as neuroprotective drugs.