CNS Drug Reviews, Vol. 4, No. 4, Winter 1998

Glutamate and aspartate play dual roles in the central nervous system as essential amino acids and the principal excitatory neurotransmitters. The theory of excitotoxicity presents the paradoxical view that these excitatory amino acids may also become endogenous neurotoxins any time the brain’s energy homeostasis is compromised (16,23,42,59). Cerebral ischemia and traumatic brain injury result in acute energy depletion and cellular depolarization. This triggers a dramatic increase in extracellular glutamate levels (10,11) due to presynaptic glutamate release and/or reversal of neuronal and glial glutamate transporters (63,64). The result is a prolonged overactivation of glutamate receptors which, through an incompletely understood cascade of events, leads to neuron death. Glutamate receptor activity is also hypothesized to play a role in the neuron death associated with chronic neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. In these latter conditions, subtle but chronic deregulation in neuronal energy metabolism renders neurons susceptible to excitotoxicity from physiological glutamate receptor activity (1,23,36). Given the premise of excitotoxicity as a central event in neuron loss associated with both acute and chronic neurodegenerative conditions, glutamate-receptor inhibition has been an aggressively pursued therapeutic strategy to treat these conditions. There are four major classes of glutamate receptors: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and metabotropic (2). Of these, NMDA receptors appears to be especially important to the excitotoxic process. The NMDA receptor is an ion channel gated by synaptically released glutamate in the presence of the coagonist glycine (29,32) and concomitant depolarization (38). The NMDA receptor is permeable to Na and Ca; it is Ca influx through the receptor that