Oxidative stress, age-related neurodegeneration, and the potential for neurotrophic treatment.

Abstract

Amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease are major human neurodegenerative disorders, the etiologies for which remain unknown. Although a unique subset of neurons is particularly affected in each of the three diseases, they have several intriguing overlapping similarities. Evidence is reviewed supporting the hypothesis that these diseases result from an inability to protect against accumulated damage by free radicals due to oxidative stress. If oxidative stress underlies or exacerbates the etiology of these diseases, then agents that effectively attenuate brain tissue lipid peroxidation or otherwise limit free radical damage may hold promise for the treatment of these neurodegenerative diseases. Although antioxidant chemical supplementation may provide effective therapy, the most effective therapy for neurodegenerative diseases may be treatment with specific neurotrophic, survival-promoting proteins. For example, brain-derived neurotrophic factor promotes survival of spinal motor neurons and mesencephalic dopaminergic neurons. One mechanism through which these proteins may exert their protection may be by stimulating endogenous defenses against oxidative stress and damage by free radicals. This hypothesis is being tested in several laboratories and provides exciting direction both for basic neurobiological research and therapeutic drug discovery.