NEUROTROPHIN REGULATION OF ENERGY HOMEOSTASIS IN THE CENTRAL-NERVOUS-SYSTEM

Our hypothesis is that one cause of neuronal cell death and shrinkage in the aged central nervous system is an inability of neurons to maint ain oxidant homeostasis in the face of increased levels of reactive ox ygen species, decreased endogenous antioxidants, and impaired energy m etabolism associated with physiological senescence, Alzheimer's, and P arkinson's diseases. Since treatment with nerve growth factor (NGF) re verses behavioral impairments in aged rats and stimulates cholinergic activity in the basal forebrain, while brain-derived neurotrophic fact or appears to play a similar role in the striatum, we propose that neu rotrophin-mediated cell-sparing reflects effects on oxidant homeostasi s. Neurotrophins may play a similar cell-sparing role in hypoxic/ische mic injury to the nervous system, which also is mediated in part by re active oxygen species. The degradation of one such species, H2O2, is c atalyzed by catalase and glutathione peroxidase (GSH Px). The activity of the latter enzyme is dependent on glutathione reductase and the av ailability of NADPH for regeneration of reduced GSH. The GSH redox cyc le is also regulated by enzymes of the hexose monophosphate shunt. NGF protects PC12 cells from H2O2 injury by stimulating the synthesis of antioxidant enzymes including catalase, GSH Px, glucose-6-phosphate de hydrogenase, and gamma-glutamylcysteine synthetase, the rate-limiting enzyme for glutathione synthesis. NGF also enhances recovery from the NAD(+) losses occurring as a consequence of H2O2 treatment.