Methamphetamine alters occludin expression via NADPH oxidase‐induced oxidative insult and intact caveolae

Journal of Cellular and Molecular Medicine

Minseon Park²  Bernhard Hennig¹ 

[1] College of Agriculture, University of Kentucky, KY, USA;Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, KY, USA

关键词: blood–brain barrier;    brain endothelial cells;    drug abuse;    methamphetamine;    oxidative stress;    tight junctions;   

DOI  :  10.1111/j.1582-4934.2011.01320.x

来源: Wiley

【 摘 要 】

Abstract

Methamphetamine (METH) is a drug of abuse with neurotoxic and vascular effects that may be mediated by reactive oxygen species (ROS). However, potential sources of METH-induced generation of ROS are not fully understood. This study is focused on the role of NAD(P)H oxidase (NOX) in METH-induced dysfunction of brain endothelial cells. Treatment with METH induced a time-dependent increase in phosphorylation of NOX subunit p47, followed by its binding with gp91 and p22, and the formation of an active NOX complex. An increase in NOX activity was associated with elevated production of ROS, alterations of occludin levels and increased transendothelial migration of monocytes. Inhibition of NOX by NSC 23766 attenuated METH-induced ROS generation, changes in occludin protein levels and monocyte migration. Because an active NOX complex is localized to caveolae, we next evaluated the role of caveolae in METH-mediated toxicity to brain endothelial cells. Treatment with METH induced phosphorylation of ERK1/2 and caveolin-1 protein. Inhibition of ERK1/2 activity or caveolin-1 silencing protected against METH-induced alterations of occludin levels. These findings indicate an important role of NOX and functional caveolae in METH-induced oxidative stress in brain endothelial cells that contribute to the subsequent alterations of occludin levels and transendothelial migration of inflammatory cells.

【 授权许可】

Unknown   
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd