Alcohol abuse and blood-brain barrier dysfunction: Underlying mechanisms

酒精滥用和血脑屏障功能障碍：潜在机制

• 批准号: 7614286
• 负责人: James Haorah
• 金额: $ 21.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614286
• 关键词: Acetaldehyde; Actins; Acute; Address; Alcohol abuse; Alcohol dehydrogenase; Alcohols; Alzheimer' s Disease; Animal Model; Antioxidants; Aorta; Astrocytes; Basement membrane; Blood; Blood - brain barrier anatomy; Brain; Calcium; Calcium Signaling; Chronic; Cognitive deficits; Complex; Cytochrome P-450 CYP2E1; Cytochrome P450; Cytoskeleton; DNA Sequence Rearrangement; Data; Disease; Encephalitis; Endothelial Cells; Endothelium; Enzymes; Ethanol; Ethanol Metabolism; Event; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Matrix Proteins; Fibroblasts; Functional disorder; Gelatinase A; Glutathione; Health; Human; ITPR1 gene; Immune response; Impairment; In Vitro; Inflammatory; Injury; Inositol; Lead; Leukocytes; Link; Lung; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Membrane; Membrane Proteins; Metabolism; Morbidity - disease rate; Multiple Sclerosis; Myosin Light Chain Kinase; Neurodegenerative Disorders; Organ; Oxidative Stress; Pathologic; Pathway interactions; Pericytes; Permeability; Pharmaceutical Preparations; Phosphorylation; Physiological; Production; Protein Tyrosine Kinase; Proteins; Rattus; Reactive Oxygen Species; Signal Pathway; Stroke; System; Testing; Tight Junctions; Toxic effect; Tyrosine Kinase Inhibitor; United States; adherent junction; alcohol effect; alcohol exposure; brain tissue; computerized data processing; feeding; in vivo; inhibitor/antagonist; kinase inhibitor; migration; monocyte; nervous system disorder; neuroinflammation; neuron loss; oxidative damage; problem drinker; stem; tripolyphosphate; white matter

DESCRIPTION (provided by applicant): Alcohol is the most commonly used and abused drug in the United States. Deleterious health effects of alcohol attribute to toxicity of internal organs including irreversible brain tissue injury. Brain tissue from chronic alcoholics exhibits neuronal cell death and degeneration paralleling neuro-cognitive deficits. Alcohol abuse leads to white matter abnormalities that could be associated with blood brain barrier (BBB) dysfunction detected in alcohol abusers or seen in animal model. The BBB formed by brain microvascular endothelial cells (BMVEC), pericytes and astrocytes connect the BMVEC assuring BBB structural tightness. The actin cytoskeleton is linked to tight junctions (TJ) proteins through intracellular zonula occludens (ZO-1-3) and this dynamic complex readily adapts to a variety of physiologic or pathologic conditions. The intracellular signaling processes that regulate phosphorylation of TJ proteins control TJ assembly and BBB integrity. The exact mechanism of BBB dysfunction seen in alcohol abusers remains elusive. We demonstrated the previously unrecognized effects of ethanol (EtOH) on BMVEC, underlying the cause of BBB impairment. We showed that EtOH increases the activity and content of EtOH-metabolizing enzymes, cytochrome P450-2E1 (CYP2E1) and alcohol dehydrogenase in human BMVEC. EtOH metabolism by CYP2E1/ADH in BMVEC enhances production of acetaldehyde (AA) and reactive oxygen species (ROS). We propose that these reactive EtOH metabolites (AA and ROS) activate myosin light chain kinase (MLCK) via IP3R-gated intracellular calcium signaling pathway resulting in phosphorylation of cytoskeletal and TJ proteins as acute effect. Further, the reactive EtOH metabolites activate matrix metalloproteinases -2 and -9 (MMP-2 and -9) via protein tyrosine kinase (PTK) signaling pathway leading to degradation of endothelial specific basement membrane (BM) or extracellular matrix (ECM) proteins. Changes in cytoskeletal and TJ assembly, or degradation of BM/ECM proteins increased BBB permeability and augmented leukocyte migration across the BBB, suggesting break down of BBB function. BBB dysfunction due to alcohol abuse could be associated with in neuro-inflammatory disorders and neurological diseases. Thus, we propose to study the mechanism of alcohol abuse disruption of blood-brain barrier due to oxidative stress stemming from alcohol metabolism in brain endothelial cells, which activates myosin light chain kinase through intracellular calcium release (acute effects) and activation of matrix metalloproteinases via PTK signaling pathway (delayed effects).

描述（由申请人提供）：酒精是美国最常用和滥用的药物。酒精归因于内部器官的毒性，包括不可逆的脑组织损伤的有害健康作用。慢性酒精中毒的脑组织表现出神经元细胞死亡和平行神经认知缺陷的变性。酗酒会导致白质异常，可能与饮酒者或动物模型中发现的血液脑屏障（BBB）功能障碍有关。由脑微血管内皮细胞（BMVEC）形成的BBB，周细胞和星形胶质细胞连接BMVEC，以确保BBB结构紧密。肌动蛋白细胞骨架与细胞内卵石阻塞（ZO-1-3）的紧密连接蛋白（TJ）蛋白有关，这种动态复合物很容易适应多种生理或病理状况。调节TJ蛋白控制TJ组装和BBB完整性的细胞内信号传导过程。在酒精滥用者中看到的BBB功能障碍的确切机制仍然难以捉摸。我们证明了乙醇（ETOH）对BMVEC的先前未识别的作用，这是BBB损害的原因。我们表明，ETOH增加了人BMVEC中ETOH代谢酶，细胞色素P450-2E1（CYP2E1）和酒精脱氢酶的活性和含量。 CYP2E1/ADH在BMVEC中的ETOH代谢增强了乙醛（AA）和活性氧（ROS）的产生。我们建议这些反应性EtOH代谢产物（AA和ROS）通过IP3R门控的细胞内钙信号通路激活肌球蛋白轻链激酶（MLCK），从而导致细胞骨架和TJ蛋白的磷酸化作为急性效应。此外，反应性ETOH代谢产物通过蛋白酪氨酸激酶（PTK）信号传导途径激活基质金属蛋白酶-2和-9（MMP -2和-9），从而导致内皮特异性基底膜（BM）或细胞外基质（ECM）蛋白质降解。 BM/ECM蛋白的细胞骨架和TJ组装的变化或降解增加了BBB的渗透性和增强BBB的白细胞迁移，这表明BBB功能分解。由于酗酒引起的BBB功能障碍可能与神经炎症性疾病和神经系统疾病有关。因此，我们建议研究由于脑内皮细胞中酒精代谢引起的氧化应激引起的酗酒滥用的机制，该机制通过PTK信号通路（延迟延迟效应）通过PTK Signaling Pathway（延迟的效果）激活肌球蛋白光链激酶，从而激活肌球蛋白光链激酶。

项目成果

Ethanol impairs glucose uptake by human astrocytes and neurons: protective effects of acetyl-L-carnitine.

• 发表时间: 2011
• 期刊: International journal of physiology, pathophysiology and pharmacology
• 作者: P. M. Abdul Muneer;Saleena Alikunju;A. Szlachetka;A. Mercer;J. Haorah

Alcohol-induced interactive phosphorylation of Src and toll-like receptor regulates the secretion of inflammatory mediators by human astrocytes.

• DOI: 10.1007/s11481-010-9213-z
• 发表时间: 2010-12
• 期刊: JOURNAL OF NEUROIMMUNE PHARMACOLOGY
• 影响因子: 6.2
• 作者: Floreani, Nicholas A.;Rump, Travis J.;Muneer, P. M. Abdul;Alikunju, Saleena;Morsey, Brenda M.;Brodie, Michael R.;Persidsky, Yuri;Haorah, James
• 通讯作者: Haorah, James

Acetyl-L-carnitine protects neuronal function from alcohol-induced oxidative damage in the brain.

• DOI: 10.1016/j.freeradbiomed.2010.08.011
• 发表时间: 2010-11-30
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Rump, Travis J.;Muneer, P. M. Abdul;Szlachetka, Adam M.;Lamb, Allyson;Haorei, Catherine;Alikunju, Saleena;Xiong, Huangui;Keblesh, James;Liu, Jianuo;Zimmerman, Matthew C.;Jones, Jocelyn;Donohue, Terrence M., Jr.;Persidsky, Yuri;Haorah, James
• 通讯作者: Haorah, James

Mechanism of alcohol-induced oxidative stress and neuronal injury.

• DOI: 10.1016/j.freeradbiomed.2008.08.030
• 发表时间: 2008-12-01
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Haorah, James;Ramirez, Servio H.;Floreani, Nicholas;Gorantla, Santhi;Morsey, Brenda;Persidsky, Yuri
• 通讯作者: Persidsky, Yuri

Inhibitory effects of alcohol on glucose transport across the blood-brain barrier leads to neurodegeneration: preventive role of acetyl-L: -carnitine.

• DOI: 10.1007/s00213-010-2076-4
• 发表时间: 2011-04
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Muneer, P. M. Abdul;Alikunju, Saleena;Szlachetka, Adam M.;Haorah, James
• 通讯作者: Haorah, James