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Published online before print October 4, 2005

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(Journal of Leukocyte Biology. 2005;78:1223-1232.)
© 2005 by Society for Leukocyte Biology

Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction

J. Haorah^*, B. Knipe^*, J. Leibhart^*, A. Ghorpade^* and Y. Persidsky^*,,1

^* Departments of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorders, and
Pathology/Microbiology, University of Nebraska Medical Center, Omaha

¹ Correspondence: Center for Neurovirology and Neurodegenerative Disorders, Departments of Pathology and Microbiology and Pharmacology and Experimental Neuroscience, 985215 Nebraska Medical Center, Omaha, NE 68198-5215. E-mail: ypersids{at}unmc.edu

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.

Key Words: tight junctions • monocyte migration

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