Excitotoxicity: perspectives based on N-methyl-D-aspartate receptor subtypes

Abstract

Since excitotoxicity has been implicated in a variety of neuropathological conditions, understanding the pathways involved in this type of cell death is of critical importance to the future clinical treatment of many diseases. The N-methyl-D-aspartate (NMDA) receptor has become a primary focus of excitotoxic research because early studies demonstrated that antagonism of this receptor subtype was neuroprotective. However, initial pharmacological agents were not clinically useful due to the adverse effects of complete NMDA receptor blockade. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. With the discovery of the basis of heterogeneity of NMDA receptors through molecular biological approaches, many new potential therapeutic targets have been uncovered, and several model systems have been developed for the study of NMDA receptor-mediated cell death. This review discusses these models and the current understanding of the relationship between NMDA receptor subtypes and excitotoxicity.