Mechanisms of Neuroprotection by Astrocytes in Alcohol Abuse

星形胶质细胞在酒精滥用中的神经保护机制

基本信息

批准号：
8243287
负责人：
James Haorah
金额：
$ 21.35万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8243287
关键词：
Acetaldehyde Acute Address Adverse effects Advocate Affect Alcohol abuse Alcohol consumption Alcoholic Intoxication Alcoholism Alcohols Animal Model Animals Antioxidants Astrocytes Biochemical Biological Markers Brain Brain region Carnitine Acyltransferases Cerebellum Cerebrum Chronic Coculture Techniques Consumption Data Defense Mechanisms Diet Drug Metabolic Detoxication Enzymes Equilibrium Ethanol Ethanol toxicity Exposure to Fetal Alcohol Syndrome Free Radicals Functional disorder Gait Ataxia Genetic Healthcare Human In Vitro Ingestion Injury Intervention Knowledge Leg Levocarnitine Acetyl Liquid substance Mediating Microglia Mitochondria Motor Motor Neurons Mus NADPH Oxidase Nerve Degeneration Neurobiology Neuroglia Neurons Neuropathy Neuroprotective Agents Nitric Oxide Oxidants Oxidative Stress Prevention Proteins Qualifying Reactive Oxygen Species Reporting Role Small Interfering RNA Stress System Therapeutic Thiamine Thiamine Deficiency Time Toxic effect Transducers Tremor Wernicke Encephalopathy Western Blotting acetaldehyde dehydrogenase alcohol effect alcohol exposure cognitive function feeding fetal human NOS2A protein in vivo innovation mouse model nervous system disorder neuron loss neuroprotection neurotoxicity novel novel therapeutic intervention oxidative damage prevent success

项目摘要

DESCRIPTION (provided by applicant): This proposal advocates the function of glial cell astrocytic acetaldehyde dehydrogenase 2 (ALDH2) as the first line neuroprotective defense mechanisms in the brain from alcohol abuse. Neutralization of reactive acetaldehyde by ALDH2 promotes the key initial protective biochemical mechanisms in alcohol abuse. The statement is supported by our recent findings that activation of NADPH oxidase and inducible nitric oxide synthase by acetaldehyde increases the levels of reactive oxygen species and nitric oxide in primary human neurons. To prevent the action of acetaldehyde as transducer for oxidative stress, a therapeutic stabilization of astrocytic ALDHs by acetyl-L-carnitine (ALC) is an innovative approach, which has not been studied so far. This protective mechanism of astrocytes is arisen from the fact that ALDHs are genuine antioxidants that can balance oxidant and antioxidant levels in alcohol stress. Our proposal is that stabilization of the inherent astrocytic ALDH2 protein in the brain shields the neurons from adverse effects of alcohol and acetaldehyde toxicity. Therefore, astrocytes are active defenders of neurons from the deleterious effects of alcohol. The central hypothesis of the proposal is that effective detoxification of acetaldehyde by ALC-stabilized astrocytic ALDH2 can prevent the oxidative damage and neurotoxicity. We propose to investigate the protective mechanisms by using primary mice and human astrocytes and neuronal co-cultures as in vitro system and chronic ethanol liquid diets feeding as our animal model. Success of the project will impact knowledge gap in unraveling the cellular and biochemical mechanisms of alcohol effects in neurobiology and health care. PUBLIC HEALTH RELEVANCE: The relevance of the proposal addresses the novelty that astrocytes are the active defenders of neurons from the deleterious effects of alcohol by virtue of their inherent ALDH2 function. Stabilization of astrocytic ALDH2 protein in brain shields the sensitive neurons from the adverse effects of alcohol toxicity. Therefore, astrocytes are the active defenders of the brain and the success of the proposal has a huge potential impact for prevention of many alcohol-related neurological disorders in health care.

描述（由申请人提供）：该提案主张神经胶质细胞星形细胞乙醛脱氢酶 2 (ALDH2) 的功能作为大脑中免受酒精滥用的第一线神经保护性防御机制。 ALDH2 中和反应性乙醛可促进酒精滥用中关键的初始保护性生化机制。我们最近的研究结果支持了这一说法，即乙醛激活 NADPH 氧化酶和诱导型一氧化氮合酶会增加人类原代神经元中活性氧和一氧化氮的水平。为了防止乙醛作为氧化应激传感器的作用，通过乙酰左旋肉碱 (ALC) 稳定星形胶质细胞 ALDH 是一种创新方法，但迄今为止尚未进行研究。星形胶质细胞的这种保护机制源于这样一个事实：ALDH 是真正的抗氧化剂，可以平衡酒精应激时的氧化剂和抗氧化剂水平。我们的建议是，大脑中固有的星形胶质细胞 ALDH2 蛋白的稳定可以保护神经元免受酒精和乙醛毒性的不利影响。因此，星形胶质细胞是神经元免受酒精有害影响的积极防御者。该提案的中心假设是，ALC 稳定的星形胶质细胞 ALDH2 对乙醛的有效解毒可以防止氧化损伤和神经毒性。我们建议通过使用原代小鼠和人类星形胶质细胞和神经元共培养物作为体外系统，并使用长期乙醇液体饮食喂养作为我们的动物模型来研究保护机制。该项目的成功将缩小在神经生物学和医疗保健领域揭示酒精影响的细胞和生化机制方面的知识差距。公共健康相关性：该提案的相关性解决了以下问题：星形胶质细胞凭借其固有的 ALDH2 功能，是神经元的积极防御者，免受酒精的有害影响。大脑中星形细胞 ALDH2 蛋白的稳定可以保护敏感神经元免受酒精毒性的不利影响。因此，星形胶质细胞是大脑的积极捍卫者，该提案的成功对于预防医疗保健中许多与酒精相关的神经系统疾病具有巨大的潜在影响。