Ethanol, 4-hydroxy-2-nonenal and the Central Nervous Sys

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DESCRIPTION (provided by applicant): Ethanol abuse is a complex disorder that has multiple societal and medical implications. The consumption of ethanol has multiple deleterious physical effects. Acute and chronic ethanol intoxication are harmful to the central nervous system (CNS). In addition to altering neurotransmission, ethanol consumption elevates oxidative damage to DNA, lipids, and proteins, and mitochondrial dysfunction. This overproduction of deleterious reactive oxygen species leads to the formation of neurotoxic products from lipid peroxidation. The long-term objective of this project is to examine the mechanisms by which the CNS metabolizes these neurotoxicants following ethanol consumption. In particular, we will study the disposition of the neurotoxic lipid peroxidation product, 4-hydroxy-2-nonenal (HNE). We hypothesize that in the CNS elevated HNE formation and decreases in HNE detoxification occur as a result of ethanol intoxication. These hypotheses will be tested in the following specific aims: (1) Determine whether levels of HNE and its metabolic products are elevated in CNS tissue in response to ethanol exposure and (2) determine whether ethanol intake impairs HNE detoxification pathways in the CNS. These studies will involve the analysis of the CNS tissue of rodents chronically exposed to ethanol as well as postmortem CNS tissue from chronic alcohol abusers. The data gathered from the successful completion of these specific aims will provide new, significant understanding how the CNS responds to long-term ethanol intoxication. These data may lead to the formation of new preventative and therapeutic strategies for ethanol-mediated neurotoxicity.