Do NMDA Antagonists Prevent Neuronal Injury? Yes.

Abstract

Available evidence suggests that pharmacologic antagonism of the N-methyl-d-aspartate (NMDA) receptor can reduce neuronal death following hypoxic-ischemic insults. This evidence is derived from experimental models, as clinical trials have not yet been completed. The observed neuroprotective effects of NMDA antagonists do not represent isolated findings, but rather they are predictions of a strong hypothesis implicating excitotoxicity—the lethal overstimulation of neuronal glutamate receptors^1,2—in the pathogenesis of hypoxicischemic central neuronal degeneration. The excitotoxicity hypothesis has received independent support from microdialysis measurements,^3,4 which indicate that during hypoxia-ischemia, extracellular glutamate levels can rise to neurotoxic concentrations.^5,6 Other supporting observations include reduced hypoxic neuronal injury following excitatory pathway deafferentation, morphologic similarities between hypoxic injury and excitotoxic injury, and the prominence of neuronal calcium overload in the pathogenesis of both conditions.^2,7,8 Although glutamate activates several receptor subtypes, the NMDA subtype may play a critical role in mediating the rapidly triggered