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

乙醇、4-羟基-2-壬烯醛和中枢神经系统

• 批准号: 6814462
• 负责人: MATTHEW J PICKLO
• 金额: $ 20.15万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6814462
• 关键词: alcoholism /alcohol abuse; aldehydes; detoxification; enzyme linked immunosorbent assay; enzyme mechanism; ethanol; free radicals; human tissue; immunocytochemistry; laboratory rat; lipid peroxides; liquid chromatography mass spectrometry; neuroprotectants; neurotoxicology; oxidative stress; peroxidation; pharmacokinetics; postmortem; western blottings

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.

描述（由申请人提供）：滥用乙醇是一种复杂的疾病，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作用。急性和慢性乙醇中毒对中枢神经系统（CNS）有害。除了改变神经传递外，乙醇消耗还提高了对DNA，脂质和蛋白质以及线粒体功能障碍的氧化损害。有害活性氧的过量生产导致脂质过氧化的神经毒性产物形成。 该项目的长期目标是检查中枢神经系统在消耗乙醇后代谢这些神经毒性的机制。 特别是，我们将研究神经毒性脂质过氧化产物4-羟基-2-非烯（HNE）的处置。我们假设在中枢神经系统中，HNE的形成升高，HNE排毒的降低是由于乙醇中毒而发生的。这些假设将在以下特定目的中进行测试：（1）确定在响应乙醇暴露的CNS组织中HNE及其代谢产物的水平是否升高，并且（2）确定乙醇摄入是否会损害CNS中HNE排毒途径。 这些研究将涉及对长期暴露于乙醇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。 从成功完成这些特定目标中收集的数据将提供新的，重要的了解中枢神经系统对长期乙醇中毒的反应。这些数据可能导致形成乙醇介导的神经毒性的新预防和治疗策略。