There is a general consensus that free radical generation leads to alterations of biochemical and biophysical properties of cell membranes and in turn, these changes may lead to pathological manifestations in aging and in degenerative diseases. Recent data from our laboratory has indicated that pro-oxidant agents may be involved in the pathogenesis of neurodegenerative diseases and that ethanol may potentiate these processes through participating in the free radical reaction. The overall objective of this project is to evaluate the hypothesis that the accelerated aging process and loss of neuronal function associated with alcohol drinking is related to the enhancement of free radical reaction by ethanol. Since activation of the glutamate receptor has been shown to cause global dementia and severe memory impairment similar to that in aging, we will use glutamate and other pro-oxidants (such as chelated iron and H2O2) as experimental tools to examine the effects of ethanol on the neurodegenerative processes.
The specific aims of this proposal are: (1) to test the hypothesis that ethanol potentiates the free radical mechanism of neurodegenerative process; (2) to investigate the involvement of oxidative insults on the aging process, and to examine how alcohol affects aging through participation in the free radical reactions and (3) to investigate possible dietary and drug interventions against the alcohol-related damage as caused by glutamate and other pro-oxidant stressors. The effects of ethanol on pro-oxidant-induced cell death and tissue damage will be examined in PC-12 cells and in C57BI/6NNIA mice, respectively. Oxidative damage will be assessed by determining cell viability, formation of thiobarbituric acid reactive substances (TBARS), lactic acid dehydrogenase (LDH) release, membrane lipid composition and activity of membrane enzymes and uptake processes (e.g. Na-pump, catecholamine uptake, etc). In addition, the ability of antioxidants (such as vitamins E and C), and drugs (Ca2+-blockers, salicylate) to protect against oxidative damage elicited by ethanol will also be investigated. It is anticipated that through this investigation, important information on the mechanism of membrane deterioration in the brain due to aging and/or alcohol intake may be obtained and preventive measures for protecting against these changes may be proposed.
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