Abstract
Brain microvascular endothelial cells (BMVEC) connected by tight junctions (TJ) form a tight monolayer at the blood-brain barrier (BBB). We investigated the idea that BBB dysfunction seen in alcohol abuse is associated with oxidative stress stemming from ethanol (EtOH) metabolism in BMVEC. Exposure to EtOH induced catalytic activity/expression of EtOH-metabolizing enzymes, which paralleled enhanced generation of reactive oxygen species (ROS). EtOH-mediated oxidative stress led to activation of myosin light chain (MLC) kinase, phosphorylation of MLC and TJ proteins, decreased BBB integrity, and enhanced monocyte migration across BBB. Acetaldehyde or ROS donors mimicked changes induced by EtOH in BMVEC. Thus, oxidative stress resulting from alcohol metabolism in BMVEC can lead to BBB breakdown in alcohol abuse, serving as an aggravating factor in neuroinflammatory disorders.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetaldehyde / pharmacology
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Adult
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Alcohol Dehydrogenase / drug effects
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Alcohol Dehydrogenase / metabolism
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Alcohol-Induced Disorders, Nervous System / metabolism
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Alcohol-Induced Disorders, Nervous System / physiopathology
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Blood-Brain Barrier / drug effects*
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Blood-Brain Barrier / metabolism
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Blood-Brain Barrier / physiopathology
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Brain / blood supply
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Brain / drug effects*
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Brain / physiopathology
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Cell Movement / drug effects
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Cell Movement / immunology
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Cells, Cultured
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Central Nervous System Depressants / adverse effects
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Cerebral Arteries / cytology
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Cerebral Arteries / drug effects*
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Cerebral Arteries / physiopathology
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Claudin-5
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Cytochrome P-450 CYP2E1 / drug effects
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Cytochrome P-450 CYP2E1 / metabolism
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Encephalitis / chemically induced
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Encephalitis / metabolism
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Encephalitis / physiopathology
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism
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Energy Metabolism / drug effects
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Energy Metabolism / physiology
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Ethanol / metabolism
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Ethanol / toxicity*
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Humans
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Membrane Proteins / drug effects
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Membrane Proteins / metabolism
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Myosin Light Chains / drug effects
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Myosin Light Chains / metabolism
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Occludin
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Oxidative Stress / drug effects*
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Oxidative Stress / physiology
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Reactive Oxygen Species / metabolism
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Reactive Oxygen Species / pharmacology
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Tight Junctions / drug effects
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Tight Junctions / metabolism
Substances
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CLDN5 protein, human
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Central Nervous System Depressants
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Claudin-5
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Membrane Proteins
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Myosin Light Chains
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OCLN protein, human
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Occludin
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Reactive Oxygen Species
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Ethanol
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Alcohol Dehydrogenase
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Cytochrome P-450 CYP2E1
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Acetaldehyde