Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation

Jeffrey J. Lochhead, Gwen McCaffrey, Colleen E. Quigley, Jessica Finch, Kristin M. Demarco, Nicole Nametz, Thomas P. Davis

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

The blood-brain barrier (BBB) has a critical role in central nervous system homeostasis. Intercellular tight junction (TJ) protein complexes of the brain microvasculature limit paracellular diffusion of substances from the blood into the brain. Hypoxia and reoxygenation (HR) is a central component to numerous disease states and pathologic conditions. We have previously shown that HR can influence the permeability of the BBB as well as the critical TJ protein occludin. During HR, free radicals are produced, which may lead to oxidative stress. Using the free radical scavenger tempol (200 mg/kg, intraperitoneal), we show that oxidative stress produced during HR (6% O 2 for 1 h, followed by room air for 20 min) mediates an increase in BBB permeability in vivo using in situ brain perfusion. We also show that these changes are associated with alterations in the structure and localization of occludin. Our data indicate that oxidative stress is associated with movement of occludin away from the TJ. Furthermore, subcellular fractionation of cerebral microvessels reveals alterations in occludin oligomeric assemblies in TJ associated with plasma membrane lipid rafts. Our data suggest that pharmacological inhibition of disease states with an HR component may help preserve BBB functional integrity.

Original languageEnglish (US)
Pages (from-to)1625-1636
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume30
Issue number9
DOIs
StatePublished - Sep 2010

Keywords

  • animal models
  • antioxidants
  • bloodbrain barrier
  • confocal microscopy
  • free radicals

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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