Ethanol, HNE, and the CNS

描述(由申请人提供)：酒精滥用是一种复杂的疾病，具有多种社会和医学影响。乙醇的消费有多种有害的物理影响。急性和慢性乙醇中毒对中枢神经系统(CNS)均有危害。除了改变神经传递，酒精消费还会增加对DNA、脂质和蛋白质的氧化损伤，以及线粒体功能障碍。这种有害的活性氧物种的过量产生会导致脂质过氧化产生神经毒性产物。该项目的长期目标是研究中枢神经系统在酒精摄入后代谢这些神经毒物的机制。 特别是，我们将研究神经毒性脂质过氧化产物4-羟基-2-壬烯醛(HNE)的处置。我们推测，在中枢神经系统中，HNE的形成增加，HNE解毒减少，这是乙醇中毒的结果。这些假说将在以下特定目标进行验证：(1)确定中枢神经系统组织中HNE及其代谢产物的水平是否因酒精暴露而升高，以及(2)确定乙醇摄入是否损害了CNS中HNE的解毒途径。这些研究将包括对长期接触酒精的啮齿动物的中枢神经系统组织以及慢性酒精滥用者的死后中枢神经系统组织的分析。 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，即中枢神经系统如何对长期酒精中毒做出反应。这些数据可能导致形成新的乙醇介导的神经毒性的预防和治疗策略。

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.