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Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?
Ann Neurol. 1992 Feb; 31(2):119-30.AN

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+Show Affiliations

Neurology Service, Massachusetts General Hospital, Boston 02114.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

1349466

Citation

Beal, M F.. "Does Impairment of Energy Metabolism Result in Excitotoxic Neuronal Death in Neurodegenerative Illnesses?" Annals of Neurology, vol. 31, no. 2, 1992, pp. 119-30.
Beal MF. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann Neurol. 1992;31(2):119-30.
Beal, M. F. (1992). Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Annals of Neurology, 31(2), 119-30.
Beal MF. Does Impairment of Energy Metabolism Result in Excitotoxic Neuronal Death in Neurodegenerative Illnesses. Ann Neurol. 1992;31(2):119-30. PubMed PMID: 1349466.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? A1 - Beal,M F, PY - 1992/2/1/pubmed PY - 1992/2/1/medline PY - 1992/2/1/entrez SP - 119 EP - 30 JF - Annals of neurology JO - Ann. Neurol. VL - 31 IS - 2 N2 - 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. SN - 0364-5134 UR - https://www.unboundmedicine.com/medline/citation/1349466/Does_impairment_of_energy_metabolism_result_in_excitotoxic_neuronal_death_in_neurodegenerative_illnesses L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0364-5134&date=1992&volume=31&issue=2&spage=119 DB - PRIME DP - Unbound Medicine ER -