Binge alcohol-induced neurodegeneration and omega-3 DHA Protection

酗酒引起的神经退行性变和 omega-3 DHA 保护

• 批准号: 7700093
• 负责人: MICHAEL A. COLLINS
• 金额: $ 32.65万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700093
• 关键词: Adolescent; Adult; Age; Alcohol abuse; Alcohol dependence; Alcohol withdrawal syndrome; Alcohol-Induced Neurotoxicity; Alcohols; Antioxidants; Apoptosis; Apoptotic; Arachidonic Acids; Biolistics; Biological Assay; Brain; Brain Edema; Brain Injuries; Chemosensitization; Chronic; Collaborations; Coupled; Diuretics; Docosahexaenoic Acids; Edema; Event; Fatty Acids; Free Radicals; Functional disorder; Hippocampus (Brain); In Vitro; Instruction; Laboratories; Laboratory Procedures; Link; Lipids; Measurement; Membrane; Modeling; National Institute on Alcohol Abuse and Alcoholism; Nerve Degeneration; Neurons; Nutritional; Omega-3 Fatty Acids; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Phosphatidylserines; Phospholipase A2; Phosphotransferases; Polyunsaturated Fatty Acids; Preparation; Publishing; Rattus; Research; Research Personnel; Risk; Signal Transduction; Site; Slice; Social Problems; Source; Supplementation; Techniques; Testing; Toxic effect; Transfection; Uncertainty; Universities; Withdrawal; addiction; adolescent alcohol abuse; aging brain; alcohol exposure; alcohol research; base; granule cell; in vivo; insight; instrumentation; male; neurobehavioral; neuroprotection; neurotoxic; phospholipase A2 inhibitor; prevent; problem drinker; research study; young adult

DESCRIPTION (provided by applicant): Prolonged alcohol abuse causes brain damage, but the mechanisms remain uncertain. From studies with adult rats in vivo and rat brain slice cultures, we know that chronic binge alcohol (ethanol) exposure and withdrawal ("alcoholic" levels, 70-120 mM) cause hippocampal/cortical neurodegeneration that (a) is not typically excitotoxic; (b) entails brain edema (diuretics prevent the edema and neurodamage); (c) involves oxidative stress (antioxidants neuroprotect); and (d) requires phospholipase A2 (PLA2) activation, which mobilizes (JO-6 arachidonic acid (AA), a free radical source (PLA2 inhibitors reduce neurodamage). Notably, u)-3 fatty acid docosahexaenoic acid (DHA) suppresses AA release and provides neuroprotection. Meanwhile, research by H.Y. Kim, NIAAA intramural investigator and DHA/alcohol research pioneer, indicates a related "lipid-based" mechanism of alcohol-induced apoptotic neurodamage involving depletion of DHA-containing phosphatidylserine (PS) and reduced pro-survival signaling that are also prevented by DHA supplementation. With Dr. Kim's collaboration, this U01 application explores functional connections between these two neurodegenerative mechanisms, and how DHA protection is realized. We propose to research three aims, posed here as questions, using adult-age (as opposed to usual adolescent) rat organotypic hippocampal/ entorhinal cortical slice cultures chronically exposed to binge alcohol/ withdrawal; techniques include biolistic transfection, antisense oligos and HPLC/MS analysis. Aim I: Are alcohol-induced reductions of membrane PS, DHA content and downstream pro-survival kinase (Akt, raf-1) activities causative events in subsequent neurodegeneration/apoptosis? Aim 2: Are alcohol-induced edema, PLA2 activation, AA mobilization and oxidative stress leading to neurodegeneration coupled to alcohol-induced changes in membrane aminophospholipids and survival kinase activities? and Aim 3: Does DHA-supplemented neuroprotection during binge alcohol entail DHA incorporation into/ potentiation of membrane PS, increased pro-survival signaling, reduced PLA2 activity and diminished AA release/oxidative stress? The lipid analyses in Aims 1 & 3 are accomplished in Dr. Kim's NIAAA laboratory; all other research is at Loyola University. RELEVANCE (See instructions): This U01 collaborative study of chronic binge alcohol's potential neuroinflammatory, lipid-based mechanisms of brain toxicity and DHA neuroprotection holds the promise of yielding nutritional and other insights that can be therapeutically valuable in reducing neurodegeneration and brain dysfunction in alcohol abuse and withdrawal.

描述（由申请人提供）：长期酗酒会导致脑损伤，但其机制仍不确定。通过对成年大鼠体内和大鼠脑切片培养的研究，我们知道长期酗酒（乙醇）暴露和戒断（“酒精”水平，70-120 mM）会导致海马/皮质神经变性，（a）通常不具有兴奋毒性； (b) 引起脑水肿（利尿剂可预防水肿和神经损伤）； (c) 涉及氧化应激（抗氧化剂神经保护）； (d) 需要磷脂酶 A2 (PLA2) 激活，从而动员 (JO-6 花生四烯酸 (AA))，一种自由基来源（PLA2 抑制剂可减少神经损伤）。值得注意的是，u)-3 脂肪酸二十二碳六烯酸 (DHA) 可抑制 AA 释放并提供神经保护。与此同时，H.Y.的研究Kim 是 NIAAA 的壁内调查员和 DHA/酒精研究先驱，他指出了酒精诱导的细胞凋亡神经损伤的“基于脂质”的相关机制，涉及含有 DHA 的磷脂酰丝氨酸 (PS) 的消耗和促生存信号传导的减少，而补充 DHA 也可以预防这种情况。在 Kim 博士的合作下，U01 应用探索了这两种神经退行性机制之间的功能联系，以及 DHA 保护是如何实现的。我们建议研究三个目标，这里作为问题提出，使用长期暴露于酗酒/戒断的成年（而不是通常的青少年）大鼠器官型海马/内嗅皮质切片培养物；技术包括基因枪转染、反义寡核苷酸和 HPLC/MS 分析。目标 I：酒精诱导的膜 PS、DHA 含量和下游促生存激酶（Akt、raf-1）活性的减少是否是随后神经变性/细胞凋亡的致病事件？目标 2：酒精引起的水肿、PLA2 激活、AA 动员和氧化应激是否会导致神经变性，并与酒精引起的膜氨基磷脂和生存激酶活性变化相结合？目标 3：酗酒期间补充 DHA 的神经保护是否需要 DHA 掺入膜 PS 或增强膜 PS、增加促生存信号传导、降低 PLA2 活性并减少 AA 释放/氧化应激？目标 1 和 3 中的脂质分析是在 Kim 博士的 NIAAA 实验室完成的；所有其他研究均在洛约拉大学进行。相关性（参见说明）： 这项 U01 合作研究针对慢性酗酒的潜在神经炎症、基于脂质的脑毒性机制和 DHA 神经保护作用，有望获得营养和其他见解，这些见解对于减少酒精滥用和戒断中的神经退行性变和脑功能障碍具有治疗价值。