Comparison of delayed administration of competitive and uncompetitive antagonists in preventing NMDA receptor-mediated neuronal death.

Abstract

Activation of N-methyl-D-aspartate (NMDA) receptors is thought to mediate toxic damage to central neurons due to hypoxia-ischemia, hypoglycemia, and trauma. We studied identified rat retinal ganglion cell neurons in vitro, a useful system for the study of excitotoxicity, and compared the protective effects of delayed administration of a competitive antagonist, 2-amino-5-phosphonovalerate (APV), and of an uncompetitive antagonist, MK-801, after glutamate-induced injury. We used maximally protective doses of the 2 antagonists. Under these conditions, both antagonists were able to prevent neuronal cell death if they were present within minutes of exposure to an endogenous glutamate-related toxin. In contrast, MK-801, but not APV, protected significantly against NMDA-mediated neurotoxicity when administered 1 to 4 hours after the initial insult. Thus, at least under certain conditions, an uncompetitive NMDA antagonist may offer a distinct advantage over a competitive antagonist when given several hours after a neurologic injury.