Aging, energy, and oxidative stress in neurodegenerative diseases.
The etiology of neurodegenerative diseases remains enigmatic; however, evidence for defects in energy metabolism, excitotoxicity, and for oxidative damage is increasingly compelling. It is likely that there is a complex interplay between these mechanisms. A defect in energy metabolism may lead to neuronal depolarization, activation of N-methyl-D-aspartate excitatory amino acid receptors, and increases in intracellular calcium, which are buffered by mitochondria. Mitochondria are the major intracellular source of free radicals, and increased mitochondrial calcium concentrations enhance free radical generation. Mitochondrial DNA is particularly susceptible to oxidative stress, and there is evidence of age-dependent damage and deterioration of respiratory enzyme activities with normal aging. This may contribute to the delayed onset and age dependence of neurodegenerative diseases. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Potential therapeutic approaches include glutamate release inhibitors, excitatory amino acid antagonists, strategies to improve mitochondrial function, free radical scavengers, and trophic factors. All of these approaches appear promising in experimental studies and are now being applied to human studies.
Beal
M F
MF
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114, USA.
D000375:Aging; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D004734:Energy Metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D009410:Nerve Degeneration; D009422:Nervous System Diseases / Q000378:metabolism / Q000503:physiopathology*; D018384:Oxidative Stress; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate