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：
8334611
负责人：
James Haorah
金额：
$ 17.63万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8334611
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.

描述（由申请人提供）：该提议提倡神经胶质细胞乙醛脱氢酶2（ALDH2）作为大脑中第一线神经保护机制在大脑中因酒精滥用而产生的。通过AldH2对反应性乙醛进行中和促进了酒精滥用中关键的初始保护性生化机制。我们最近的发现支持了这一说法，即通过乙醛激活NADPH氧化酶和诱导的一氧化氮合酶会增加原发性人类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的传感器的作用，乙酰基-L-肉碱（ALC）对星形胶质细胞ALDH的治疗稳定是一种创新的方法，到目前为止尚未研究。这种星形胶质细胞的保护机制是由于ALDH是真正的抗氧化剂，可以在酒精胁迫下平衡氧化剂和抗氧化剂水平。我们的建议是，大脑中固有的星形细胞ALDH2蛋白的稳定使神经元免受酒精和乙醛毒性的不良反应。因此，星形胶质细胞是因酒精的有害作用而活跃的神经元捍卫者。该提案的中心假设是，通过ALC稳定的星形胶质细胞ALDH2对乙醛有效排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作为体外系统和慢性乙醇液体饮食作为我们的动物模型来研究保护机制。该项目的成功将影响知识差距，以揭示酒精效应在神经生物学和医疗保健中的细胞和生化机制。