OXIDATIVE DAMAGE, DNA, AND ETHANOL WITHDRAWAL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Withdrawal from ethanol use poses unique clinical manifestations, including life-treatening seizures and hyperactivity that require emergency intervention and hospitalization. Multiple episodes of ethanol withdrawal are associated with poor memory performance, indicative of long-term CNS deficits. Ethanol withdrawal is associated with elevated oxidative damage to lipids in the brain. The long term goal of this work is to define the role of lipid peroxidation as neurotoxic sequelae of ethanol abuse and withdrawal. The objective of this proposal is to validate the extent to which peroxidation products of docosahexaenoic acid (DHA; 22:6, n-3) are elevated as a result of ethanol withdrawal. These data will be used for the development and assessment of better anti-withdrawal therapies and determining the biochemical mechanisms of toxicity. DHA is the most abundant polyunsaturated fatty acid in the brain and is concentrated in neuronal terminals. DHA has many important functions in the brain. Our initial data show that oxidative damage to DHA, assessed by F4-neuroprostanes (NeuroPs), occurs in the cerebral cortex of rats undergoing ethanol withdrawal. We demonstrate that trans-4-hydroxy-2-hexenal (HHE), a major unsaturated aldehyde product of DHA peroxidation, is toxic to rat cerebral cortical neurons and depletes neuronal glutathione. Our working hypothesis is that oxidative damage to DHA is elevated during the progression of ethanol withdrawal. This hypothesis will be tested through successful completion of the following aim: Define the progression of NeuroP and HHE formation as a result of ethanol intoxication and withdrawal.