OXIDATIVE DAMAGE, DNA, AND ETHANOL WITHDRAWAL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 停止使用乙醇会造成独特的临床表现，包括危及生命的癫痫发作和需要紧急干预和住院治疗的多动症。 多次乙醇戒断与记忆力低下有关，提示长期CNS缺陷。 乙醇戒断与脑中脂质氧化损伤升高有关。 这项工作的长期目标是确定脂质过氧化作为酒精滥用和戒断的神经毒性后遗症的作用。 本提案的目的是验证二十二碳六烯酸（DHA; 22：6，n-3）的过氧化产物因乙醇提取而升高的程度。 这些数据将用于开发和评估更好的抗戒断治疗，并确定毒性的生化机制。 DHA是大脑中含量最丰富的多不饱和脂肪酸，集中在神经末梢。 DHA在大脑中有许多重要的功能。 我们的初步数据表明，DHA的氧化损伤，评估F4-神经前列腺素（NeuroPs），发生在大脑皮层的大鼠经历乙醇戒断。 我们证明，反式-4-羟基-2-己烯醛（HHE），一个主要的不饱和醛产品的DHA过氧化反应，是有毒的大鼠大脑皮层神经元和耗尽神经元谷胱甘肽。 我们的工作假设是，在乙醇戒断过程中，DHA的氧化损伤升高。 将通过成功完成以下目标来检验这一假设：定义乙醇中毒和戒断导致的NeuroP和HHE形成的进展。

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.