Binge alcohol-induced neurodamage and omega-3 DHA Protection

酗酒引起的神经损伤和 omega-3 DHA 保护

• 批准号: 9234450
• 负责人: MICHAEL A. COLLINS
• 金额: $ 33.98万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-06 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234450
• 关键词: AQP1 gene; Adult; Age; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Attention; Blood alcohol level measurement; Brain; Brain Edema; Brain Injuries; Cells; Chronic; Cognitive; Collaborations; DNA Damage; Dementia; Docosahexaenoic Acids; Edema; Ethanol; Event; Fatty Acids; Fish Oils; Health; Hippocampus (Brain); Impaired cognition; In Vitro; Inflammatory; Intoxication; Laboratories; Lead; Link; Lipid Binding; Lipids; Marines; Membrane; Metabolism; Modeling; National Institute on Alcohol Abuse and Alcoholism; Necrosis; Nerve Degeneration; Neurocognitive; Neuroglia; Neuroimmune; Neurons; Neuroprotective Agents; Nuclear; Omega-3 Fatty Acids; Outcome; Oxidative Stress; Oxidative Stress Pathway; Pathologic Processes; Pathway interactions; Peroxides; Phospholipase; Phospholipase A2; Phospholipids; Poly(ADP-ribose) Polymerases; Process; Protein Isoforms; Proteins; RNA Interference; Rattus; Reactive Oxygen Species; Research Personnel; Research Support; Role; Route; Signal Transduction; Slice; Supplementation; Swelling; Toll-like receptors; alcohol exposure; alcoholism therapy; aquaporin 4; base; cytokine; experimental study; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; insight; male; neuroinflammation; neuron loss; neuroprotection; neurotoxic; novel; oxidative DNA damage; peroxidation; prevent; problem drinker; public health relevance; repaired; response; water channel

DESCRIPTION (provided by applicant): Chronic alcohol (ethanol) abuse, especially binge-type alcoholism, causes brain damage by unresolved mechanisms. Adult rats exposed to high blood alcohol levels via repeated binges incur hippocampal (HC) and entorhinal cortical (EC) neurodegeneration that is conceivably downstream of brain edema, neuroinflammation and oxidative stress (OxS). Our collaborative studies with Dr. Hee-Yong Kim at NIAAA and others, which have utilized an adult male rat model and a parallel in vitro model (rat organotypic HC-EC slice cultures), provide evidence that binge alcohol activates OxS and edema-related, phospholipid-linked pro-oxidative pathways via previously unacknowledged neuroinflammatory routes. The specific proteins activated, quite likely in different cells, include aquaporin-4 (AQP4, poly (ADP-ribose) polymerase-1 (PARP-1), and certain phospholipase A2 (PLA2) isoforms that mobilize excessive ω6 arachidonic acid (ARA) to generate OxS. Furthermore, ω3 docosahexaenoic acid (DHA), possibly via several mechanisms, is potently anti-inflammatory and neuroprotective in the cultures. In continued collaboration with Dr. Kim's laboratory, we will explore the signaling between these factors with an expanded neuroinflammatory hypothesis: PARP-1 and AQP4 are the critical "1st response" proteins that govern distinct binge alcohol-dependent neuroinflammatory pathways-with PARP-1 sensing initial DNA oxidative damage/strand breaks from alcohol-generated OxS, becoming hyper-elevated, and triggering PLA2-derived excessive ARA release, while the increased AQP4 promotes brain edema, DHA loss and Akt reductions to elicit more OxS, with both paths coalescing in neurodamage; supplemented DHA then promotes antioxidative suppression of these pathways and neuroprotection via mechanisms that may involve both its free and lipid-bound forms. Three aims are proposed: the first two aims use binge alcohol-treated adult-age HC-EC slice cultures (newly developed in our current studies), while aim 3 extrapolates in vitro results to a fitting in vivo model, repetitive binge intoxication of adult male rats (Majchrowicz model)-a model in which neurodegeneration was first characterized in our laboratories and is being used by NIAAA investigators. AIM 1 examines how PARP-1, AQP4 and PLA2 are regulated by alcohol and relate to each other and to neurodegeneration, using specific inhibitors and RNA interference; AIM 2 probes supplemental DHA's mechanisms that preclude alcohol- dependent neuroinflammatory phospholipid mechanisms while achieving neuroprotection, including its membrane phospholipid incorporation as well as its metabolism to protective resolvins and neuroprotectin-1; and AIM 3 extends results from Aim 1 and 2 experiments to the rat binge model, examining our binge alcohol/PARP-1 "cascade" hypothesis and DHA's neuroprotective mechanism in vivo. The results could shed insight into novel neuroinflammatory/neurotoxic alcohol mechanisms, and clarify how DHA supplementation might be cognitively beneficial as adjunct therapy in alcoholism treatment.

描述（由申请人提供）：慢性酒精（乙醇）滥用，特别是暴饮暴食型酒精中毒，通过未解决的机制导致脑损伤。成年大鼠通过反复狂欢暴露于高血液酒精水平引起海马（HC）和内嗅皮质（EC）神经变性，这是可以想象的脑水肿，神经炎症和氧化应激（OxS）的下游。我们与NIAAA的Hee-Yong Kim博士和其他人的合作研究利用了成年雄性大鼠模型和平行的体外模型（大鼠器官型HC-EC切片培养物），提供了酗酒通过以前未被承认的神经炎症途径激活OxS和水肿相关的磷脂相关促氧化途径的证据。在不同细胞中激活的特异性蛋白质包括水通道蛋白-4（AQP 4）、聚（ADP-核糖）聚合酶-1（PARP-1）和某些磷脂酶A2（PLA 2）亚型，这些亚型可动员过量的ω6花生四烯酸（ARA）产生OxS。此外，ω3二十二碳六烯酸（DHA），可能通过几种机制，在培养物中具有强效抗炎和神经保护作用。在与Kim博士实验室的持续合作中，我们将通过扩展的神经炎症假说探索这些因素之间的信号传导：PARP-1和AQP 4是关键的“第一反应”蛋白，其控制不同的酗酒依赖性神经炎症途径-PARP-1感知来自酒精产生的OxS的初始DNA氧化损伤/链断裂，变得过度升高，并触发PLA 2衍生的过量ARA释放，而增加的AQP 4促进脑水肿、DHA损失和Akt减少以引起更多的OxS，两种途径在神经损伤中合并;补充的DHA然后通过可能涉及其游离和脂质结合形式的机制促进这些途径的抗氧化抑制和神经保护。提出了三个目标：前两个目标使用酗酒处理的成年人HC-EC切片培养物（我们目前的研究中新开发的），而目标3将体外结果外推到一个合适的水平。 体内模型，成年雄性大鼠的重复性狂欢中毒（Majchrowicz模型）-一种神经变性首先在我们的实验室中表征并由NIAAA研究者使用的模型。AIM 1使用特异性抑制剂和RNA干扰来检测PARP-1、AQP 4和PLA 2如何受酒精调节，以及它们如何相互关联并与神经变性相关; AIM 2探索补充DHA的机制，其在实现神经保护的同时排除酒精依赖性神经炎性磷脂机制，包括其膜磷脂掺入以及其代谢为保护性消退素和神经保护素-1; AIM 3将目标1和目标2实验的结果扩展到大鼠狂饮模型，检验我们的狂饮酒精/PARP-1“级联”假说和DHA的体内神经保护机制。这些结果可以深入了解新的神经炎症/神经毒性酒精机制，并阐明DHA补充剂如何作为酒精中毒治疗的辅助疗法在认知方面有益。