Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions

Claire L Gibson, Kirtiman Srivastava, Nikola Sprigg, Philip M W Bath, Ulvi Bayraktutan

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Ischaemic strokes evoke blood-brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho-kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho-kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil- versus vehicle-treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post-ischaemia or 4 h post-ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress- and tight junction-related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen-glucose deprivation ± reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin-5. Cotreatment of cells with Y-27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho-kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions. Inhibition of Rho-kinase (ROCK) activity in a mouse model of human ischaemic stroke significantly improved functional outcome while reducing cerebral lesion and oedema volumes compared to vehicle-treated counterparts. Studies conducted with brain microvascular endothelial cells exposed to OGD ± R in the presence of Y-27632 revealed restoration of intercellular junctions and suppression of prooxidant NADPH oxidase activity as important factors in ROCK inhibition-mediated BBB protection.

Original languageEnglish
Pages (from-to)816-26
Number of pages11
JournalJournal of Neurochemistry
Volume129
Issue number5
Early online date18 Mar 2014
DOIs
Publication statusPublished - Jun 2014

Keywords

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Amides
  • Animals
  • Astrocytes
  • Blood-Brain Barrier
  • Blotting, Western
  • Brain Chemistry
  • Brain Ischemia
  • Cells, Cultured
  • Cerebral Infarction
  • Endothelial Cells
  • Functional Laterality
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NADPH Oxidase
  • Nerve Tissue Proteins
  • Oxidative Stress
  • Protein Kinase Inhibitors
  • Psychomotor Performance
  • Pyridines
  • Reactive Oxygen Species
  • Tight Junctions
  • rho-Associated Kinases

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