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。酒精对健康的有害影响归因于内脏器官的毒性，包括不可逆的脑组织损伤。慢性酗酒者的脑组织表现出与神经认知缺陷并行的神经元细胞死亡和退化。酒精滥用会导致白质异常，这可能与酒精滥用者中检测到的或动物模型中发现的血脑屏障（BBB）功能障碍有关。由脑微血管内皮细胞 (BMVEC)、周细胞和星形胶质细胞形成的 BBB 连接 BMVEC，确保 BBB 结构的紧密性。肌动蛋白细胞骨架通过细胞内闭锁带 (ZO-1-3) 与紧密连接 (TJ) 蛋白连接，这种动态复合物很容易适应各种生理或病理条件。调节 TJ 蛋白磷酸化的细胞内信号传导过程控制着 TJ 组装和 BBB 完整性。酗酒者血脑屏障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 的先前未被认识的影响，这是 BBB 损伤的根本原因。我们发现，EtOH 会增加人 BMVEC 中 EtOH 代谢酶、细胞色素 P450-2E1 (CYP2E1) 和乙醇脱氢酶的活性和含量。 BMVEC 中 CYP2E1/ADH 的乙醇代谢增强了乙醛 (AA) 和活性氧 (ROS) 的产生。我们提出这些反应性乙醇代谢物（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），导致细胞骨架和 TJ 蛋白磷酸化作为急性效应。此外，反应性 EtOH 代谢物通过蛋白酪氨酸激酶 (PTK) 信号通路激活基质金属蛋白酶 -2 和 -9（MMP-2 和 -9），导致内皮特异性基底膜 (BM) 或细胞外基质 (ECM) 蛋白降解。细胞骨架和 TJ 组装的变化或 BM/ECM 蛋白的降解增加了 BBB 通透性并增强了白细胞跨 BBB 的迁移，表明 BBB 功能被破坏。酗酒导致的血脑屏障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产生的氧化应激导致的酒精滥用破坏血脑屏障的机制，该氧化应激通过细胞内钙释放（急性作用）激活肌球蛋白轻链激酶，并通过基质金属蛋白酶的激活PTK信号通路（延迟效应）。

项目成果

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

酒精诱导的 Src 和 Toll 样受体的相互作用磷酸化调节人星形胶质细胞炎症介质的分泌。

• 发表时间: 2010-12
• 作者: Floreani, Nicholas A;Rump, Travis J;Abdul Muneer, P M;Alikunju, Saleena;Morsey, Brenda M;Brodie, Michael R;Persidsky, Yuri;Haorah, James
• 通讯作者: Haorah, James

Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects.

老年受试者在夜间服用一次唑吡坦和佐匹克隆后，同样会损害单调的驾驶表现。

• 发表时间: 2011-04
• 影响因子: 3.4
• 作者: Bocca, Marie;Marie, Sullivan;Lelong;Bertran, Françoise;Couque, Colette;Desfemmes, Tsellina;Berthelon, Catherine;Amato, Jean;Moessinger, Michèle;Paillet;Coquerel, Antoine;Denise, Pierre
• 通讯作者: Denise, Pierre

The inflammatory footprints of alcohol-induced oxidative damage in neurovascular components.

酒精引起的神经血管成分氧化损伤的炎症足迹。

• 发表时间: 2011-06
• 作者: Alikunju, Saleena;Muneer, P. M. Abdul;Zhang, Yan;Szlachetka, Adam M.;Haorah, James
• 通讯作者: Haorah, James

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

乙酰左旋肉碱可保护神经元功能免受酒精引起的大脑氧化损伤。

• DOI: 10.1016/j.freeradbiomed.2010.08.011
• 发表时间: 2010-11-30
• 期刊: Free radical biology & 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

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

酒精对葡萄糖穿过血脑屏障转运的抑制作用导致神经变性：乙酰-L:-肉碱的预防作用。

• 发表时间: 2011-04
• 影响因子: 3.4
• 作者: Abdul Muneer, P M;Alikunju, Saleena;Szlachetka, Adam M;Haorah, James
• 通讯作者: Haorah, James