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

Gibson, Claire L.; Srivastava, Kirtiman; Sprigg, Nikola; Bath, Philip M.W.; Bayrakutan, Ulvi

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.

Citation

Gibson, C. L., Srivastava, K., Sprigg, N., Bath, P. M., & Bayrakutan, U. (in press). Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. Journal of Neurochemistry, 129(5), https://doi.org/10.1111/jnc.12681

• Journal Article Type: Article
• Acceptance Date: Feb 7, 2014
• Online Publication Date: Mar 18, 2014
• Deposit Date: Oct 27, 2016
• Publicly Available Date: Oct 27, 2016
• Journal: Journal of Neurochemistry
• Print ISSN: 0022-3042
• Electronic ISSN: 1471-4159
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 129
• Issue: 5
• DOI: https://doi.org/10.1111/jnc.12681
• Public URL: https://nottingham-repository.worktribe.com/output/724781
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1111/jnc.12681/abstract
• Additional Information: This is the peer reviewed version of the following article: Gibson, Claire L. and Srivastava, Kirtiman and Sprigg, Nikola and Bath, Philip M. W. and Bayraktutan, Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions,; Journal of Neurochemistry (2014), v. 129, no. 5, pp. 816-826 which has been published in final form at http://onlinelibrary.com.doi/10.1111/jnc.12681. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.