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dc.contributor.authorNiego, B
dc.contributor.authorLee, N
dc.contributor.authorLarsson, P
dc.contributor.authorde Silva, TM
dc.contributor.authorAu, AE-L
dc.contributor.authorMcCutcheon, F
dc.contributor.authorMedcalf, RL
dc.date.accessioned2021-02-04T01:38:28Z
dc.date.available2021-02-04T01:38:28Z
dc.date.issued2017-05-16
dc.identifierpii: PONE-D-17-01290
dc.identifier.citationNiego, B., Lee, N., Larsson, P., de Silva, T. M., Au, A. E. -L., McCutcheon, F. & Medcalf, R. L. (2017). Selective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin. PLOS ONE, 12 (5), https://doi.org/10.1371/journal.pone.0177332.
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11343/259429
dc.description.abstractRho-kinase (ROCK) inhibition, broadly utilised in cardiovascular disease, may protect the blood-brain barrier (BBB) during thrombolysis from rt-PA-induced damage. While the use of nonselective ROCK inhibitors like fasudil together with rt-PA may be hindered by possible hypotensive side-effects and inadequate capacity to block detrimental rt-PA activity in brain endothelial cells (BECs), selective ROCK-2 inhibition may overcome these limitations. Here, we examined ROCK-2 expression in major brain cells and compared the ability of fasudil and KD025, a selective ROCK-2 inhibitor, to attenuate rt-PA-induced BBB impairment in an in vitro human model. ROCK-2 was highly expressed relative to ROCK-1 in all human and mouse brain cell types and particularly enriched in rodent brain endothelial cells and astrocytes compared to neurons. KD025 was more potent than fasudil in attenuation of rt-PA- and plasminogen-induced BBB permeation under normoxia, but especially under stroke-like conditions. Importantly, only KD025, but not fasudil, was able to block rt-PA-dependent permeability increases, morphology changes and tight junction degradation in isolated BECs. Selective ROCK-2 inhibition further diminished rt-PA-triggered myosin phosphorylation, shape alterations and matrix metalloprotease activation in astrocytes. These findings highlight ROCK-2 as the key isoform driving BBB impairment and brain endothelial damage by rt-PA and the potential of KD025 to optimally protect the BBB during thrombolysis.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleSelective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pone.0177332
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titlePLoS One
melbourne.source.volume12
melbourne.source.issue5
dc.rights.licenseCC BY
melbourne.elementsid1214084
melbourne.contributor.authorAu, Amanda
dc.identifier.eissn1932-6203
melbourne.accessrightsOpen Access


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