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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

Authors

Kirtiman Srivastava

NIKOLA SPRIGG nikola.sprigg@nottingham.ac.uk
Professor of Stroke Medicine

Philip M.W. Bath



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 http://eprints.nottingham.ac.uk/id/eprint/38002
Publisher URL http://onlinelibrary.wiley.com/doi/10.1111/jnc.12681/abstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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