Claire L. Gibson
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
Nikola Sprigg Nikola.Sprigg@nottingham.ac.uk
Philip M.W. Bath
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.
|Journal Article Type||Article|
|Journal||Journal of Neurochemistry|
|Peer Reviewed||Peer Reviewed|
|APA6 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), doi:10.1111/jnc.12681|
|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.
Inhibition of Rho-kinase protects cerebral barrier from ischemia-evoked injury through modulations of endothelial cell oxidative stress and tight jun.pdf
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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