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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.
J Neurochem. 2014 Jun; 129(5):816-26.JN

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.

Authors+Show Affiliations

School of Psychology, University of Leicester, Leicester, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24528233

Citation

Gibson, Claire L., et al. "Inhibition of Rho-kinase Protects Cerebral Barrier From Ischaemia-evoked Injury Through Modulations of Endothelial Cell Oxidative Stress and Tight Junctions." Journal of Neurochemistry, vol. 129, no. 5, 2014, pp. 816-26.
Gibson CL, Srivastava K, Sprigg N, et al. Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. J Neurochem. 2014;129(5):816-26.
Gibson, C. L., Srivastava, K., Sprigg, N., Bath, P. M., & Bayraktutan, U. (2014). 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), 816-26. https://doi.org/10.1111/jnc.12681
Gibson CL, et al. Inhibition of Rho-kinase Protects Cerebral Barrier From Ischaemia-evoked Injury Through Modulations of Endothelial Cell Oxidative Stress and Tight Junctions. J Neurochem. 2014;129(5):816-26. PubMed PMID: 24528233.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. AU - Gibson,Claire L, AU - Srivastava,Kirtiman, AU - Sprigg,Nikola, AU - Bath,Philip M W, AU - Bayraktutan,Ulvi, Y1 - 2014/03/18/ PY - 2013/11/25/received PY - 2014/01/20/revised PY - 2014/02/07/accepted PY - 2014/2/18/entrez PY - 2014/2/18/pubmed PY - 2014/7/11/medline KW - Rho-kinase inhibitor KW - blood-brain barrier KW - brain microvascular endothelial cells KW - brain oedema KW - ischaemic stroke KW - oxidative stress SP - 816 EP - 26 JF - Journal of neurochemistry JO - J. Neurochem. VL - 129 IS - 5 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/24528233/Inhibition_of_Rho_kinase_protects_cerebral_barrier_from_ischaemia_evoked_injury_through_modulations_of_endothelial_cell_oxidative_stress_and_tight_junctions_ L2 - https://doi.org/10.1111/jnc.12681 DB - PRIME DP - Unbound Medicine ER -