Neurodegenerative disorders: clues from glutamate and energy metabolism

It is well established that glutamate receptors play a major role in mediating acute ischemic neuronal degeneration in the CNS. Cerebral ischemia and head or spinal cord trauma are associated with excessive release and extracellular accumulation of glutamate, which leads to persistent activation of glutamate receptors and acute neurotoxic degeneration of the hyperstimulated neuron. It has been more difficult to link neuronal degeneration that occurs in chronic neurodegenerative disorders to an excitotoxic mechanism. However, accumulating evidence suggests that impairment of intracellular energy metabolism associated with hyperactivation of glutamate receptors may be a common mechanism contributing to neuronal death in such disorders. It is proposed that impaired energy metabolism results in deterioration of membrane function and loss of the voltage-dependent Mg2+ block of N-methyl-D-aspartate receptors, which allows persistent activation of these receptors by glutamate, even if concentrations of glutamate at the receptor are within the normal physiological range. Studies in rodents using mitochondrial respiratory chain toxins, such as aminooxyacetic acid, 1-methyl-4-phenylpyridinium ion, malonic acid, and 3-nitropropionic acid, suggest that these agents do induce CNS degeneration by a process involving an excitotoxic mechanism. Striatal and nigral degeneration induced by mitochondrial toxins in rodents resembles neuropathology seen in humans suffering from Huntington's or Parkinson's disease and can be attenuated by glutamate receptor antagonists and agents that improve energy metabolism. Such experimental observations suggest that disturbed energy metabolism and glutamate may be involved in neuronal death leading to abiotrophic/neurodegenerative disorders in humans. If so, glutamate antagonists or agents that improve energy metabolism may slow the degenerative process and offer a therapeutic approach for temporarily retarding the progression of these disabling disorders.