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: 7942047
• 负责人: MICHAEL A. COLLINS
• 金额: $ 33.46万
• 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/7942047
• 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，但其机制尚不清楚。从成年大鼠体内和大鼠脑切片培养的研究中，我们知道慢性酗酒（乙醇）暴露和戒断（“酒精”水平，70-120毫米）会导致海马/皮质神经变性(a)通常不是兴奋性毒性的；(b)引起脑水肿（利尿剂可防止水肿和神经损伤）；(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，其调动(JO-6花生四烯酸（AA），一种自由基来源（PLA2抑制剂减少神经损伤）。值得注意的是，u)-3脂肪酸二十二碳六烯酸（DHA）抑制AA释放并提供神经保护。同时，NIAAA内部研究员和DHA/酒精研究先驱H.Y. Kim的研究表明，酒精诱导的凋亡性神经损伤的相关“基于脂质”的机制涉及含有DHA的磷脂酰丝氨酸（PS）的消耗和促生存信号的减少，这也可以通过补充DHA来预防。在Kim博士的合作下，这个U01应用程序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，在这里提出的问题，使用成年（而不是通常的青春期）大鼠器官型海马/内嗅皮层切片培养长期暴露于酗酒/戒断；技术包括生物转染，反义寡核苷酸和高效液相色谱/质谱分析。目的1：酒精诱导的膜PS、DHA含量和下游促生存激酶（Akt、raf-1）活性的降低是否导致随后的神经退行性/凋亡？目的2：酒精诱导的水肿、PLA2激活、AA动员和氧化应激导致的神经退行性变是否与酒精诱导的膜氨基磷脂和存活激酶活性的变化相关联？目的3：狂饮期间DHA补充的神经保护是否会导致DHA掺入/增强膜PS，增加促生存信号，降低PLA2活性和减少AA释放/氧化应激？目的1和3的脂质分析在Kim博士的NIAAA实验室完成；其他的研究都在洛约拉大学进行。相关性（见说明）：这项U01合作研究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，有望在减少酒精滥用和戒断时的神经变性和脑功能障碍方面产生营养和其他有治疗价值的见解。