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

Minseon Park, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)362-375
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • Blood-brain barrier
  • Brain endothelial cells
  • Drug abuse
  • Methamphetamine
  • Oxidative stress
  • Tight junctions

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine

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