Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction.
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.
Haorah
J
J
Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Knipe
B
B
Leibhart
J
J
Ghorpade
A
A
Persidsky
Y
Y
D000079:Acetaldehyde / Q000494:pharmacology; D000328:Adult; D000426:Alcohol Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000009:adverse effects; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D062507:Claudin-5; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000187:drug effects / Q000378:metabolism; D062793:Occludin; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
C107466:CLDN5 protein, human; D002492:Central Nervous System Depressants; D062507:Claudin-5; D008565:Membrane Proteins; D018994:Myosin Light Chains; C568985:OCLN protein, human; D062793:Occludin; D017382:Reactive Oxygen Species; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D000079:Acetaldehyde