Ethanol, HNE, and the CNS

描述（由申请人提供）：乙醇滥用是一种复杂的疾病，具有多种社会和医学影响。乙醇的消耗具有多种有害的物理效应。急性和慢性乙醇中毒对中枢神经系统（CNS）有损害。除了改变神经传递外，乙醇消耗还增加了对DNA、脂质和蛋白质的氧化损伤以及线粒体功能障碍。这种有害活性氧的过度产生导致脂质过氧化形成神经毒性产物。 本项目的长期目标是研究中枢神经系统代谢这些神经毒物的机制。 特别是，我们将研究处置的神经毒性脂质过氧化产物，4-羟基-2-壬烯醛（HNE）。我们推测，在中枢神经系统中，乙醇中毒导致HNE形成增加和HNE解毒减少。这些假设将在以下特定目的中进行检验：（1）确定CNS组织中HNE及其代谢产物的水平是否因乙醇暴露而升高，以及（2）确定乙醇摄入是否损害CNS中的HNE解毒途径。 这些研究将涉及分析长期暴露于乙醇的啮齿动物的CNS组织以及长期酒精滥用者的死后CNS组织。 从这些特定目标的成功完成中收集的数据将提供新的，重要的理解中枢神经系统如何对长期乙醇中毒作出反应。这些数据可能导致乙醇介导的神经毒性的新的预防和治疗策略的形成。

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.