Do NMDA Antagonists Prevent Neuronal Injury? No.

L-glutamate, a major excitatory amino acid neurotransmitter, rather surprisingly appears to act as an endogenous neurotoxin. 1 The excitotoxic hypothesis postulates that abnormal levels of excitatory amino acids occur and, by excessive synaptic stimulation, drive neurons to a premature death. 2 Cell culture observation has implicated calcium flux through the N -methyl-d-aspartate (NMDA) linked ionophore as the critical metabolic event 3 leading to the conjecture that NMDA antagonists will prevent neuronal injury. 4 Most of the evidence that supports this belief is derived from hypoxic-ischemia—related experimentation, but attempts have been made to generalize the theory and practice of NMDA antagonism to other neurologic disease processes and their treatment.5 Models of diseases such as Parkinson's disease, Alzheimer's disease, and motor neuron disease are compromised by our current lack of understanding of the molecular basis of their etiology and their link to pathologically elevated glutamate levels is at best