Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?

Abstract

The etiology of nerve cell death in neuronal degenerative disease is unknown, but it has been hypothesized that excitotoxic mechanisms may play a role. Such mechanisms may play a role in diseases such as Huntington's disease, Parkinson's disease, amyotropic lateral sclerosis, and Alzheimer's disease. In these illnesses, the slowly evolving neuronal death is unlikely to be due to a sudden release of glutamate, such as occurs in ischemia. One possibility, however, is that a defect in mitochondrial energy metabolism could secondarily lead to slow excitotoxic neuronal death, by making neurons more vulnerable to endogenous glutamate. With reduced oxidative metabolism and partial cell membrane depolarization, voltage-dependent N-methyl-D-aspartate (NMDA) receptor ion channels would be more easily activated. In addition, several other processes involved in buffering intracellular calcium may be impaired. Recent studies in experimental animals showed that mitochondrial toxins can result in a pattern of neuronal degeneration closely resembling that seen in Huntington's disease, which can be blocked with NMDA antagonists. NMDA antagonists also block neuronal degeneration induced by 1-methyl-4-phenylpyridium, which has been implicated in experimental models of Parkinson's disease. The delayed onset of neurodegenerative illnesses could be related to the progressive impairment of mitochondrial oxidative phosphorylation, which accompanies normal aging. If defective mitochondrial energy metabolism plays a role in cell death in neurodegenerative disorders, potential therapeutic strategies would be to use excitatory amino acid antagonists or agents to bypass bioenergetic defects.

• Authors: M F Beal
• Journal: Annals of neurology (Ann Neurol) Vol. 31 Issue 2 Pg. 119-30 (Feb 1992) ISSN: 0364-5134 [Print] United States
• PMID: 1349466 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Glutamates
• Neurotoxins
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid

Topics

• Aging (metabolism, pathology)
• Alzheimer Disease (metabolism, pathology)
• Animals
• Brain Diseases (metabolism, pathology)
• Cell Death
• Energy Metabolism
• Glutamates (metabolism)
• Glutamic Acid
• Humans
• Huntington Disease (metabolism, pathology)
• Ion Channel Gating
• MPTP Poisoning
• Mitochondria (metabolism)
• Models, Biological
• Nerve Degeneration
• Neurons (metabolism, pathology)
• Neurotoxins (metabolism)
• Oxidative Phosphorylation
• Parkinson Disease (metabolism, pathology)
• Parkinson Disease, Secondary (metabolism, pathology)
• Primates
• Rats
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)