Energy Failure, Glutamate and Neuropathology: Relevance to Neurodegenerative Disorders
Impairment of energy metabolism resulting in deterioration of the function of membranes, leading to loss of the Mg2+ block on N-methyl-D-aspartate (NMDA) receptors, allowing persistent activation of these receptors by endogenous glutamate is postulated as a mechanism to explain slow neuronal death in neurodegenerative disorders. Studies in rodents with mitochondrial respiratory chain toxins, aminoox-yacetic acid, 1-methyl-4-phenylpyridinium ion, and 3-nitropropionic acid, suggest that such mechanisms may indeed be involved in neurotoxicity produced by these agents. Nigral and striatal neurotoxicity induced by mitochondrial toxins in rodents reproduces neuropathology similar to that seen in humans suffering from Parkinson’s or Huntington’s disease, and can be prevented by NMDA receptor antagonists. Such observations indicate that glutamate may be involved in slow neuronal death leading to abiotrophic disorders and suggest the use of glutamate antagonists as potential neuroprotective agents to prevent or retard neuronal damage and death in relevant regions of the brain. Such an approach would consequently slow the rate of progression of these disabling disorders.
KeywordsNMDA Receptor NMDA Antagonist Energy Failure Mitochondrial Energy Metabolism Excitotoxic Lesion
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