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Selective inhibitio...
Selective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin
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Niego, B. (författare)
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Lee, N. (författare)
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- Larsson, Pia, 1978 (författare)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory
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de Silva, T. M. (författare)
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Au, A. E. L. (författare)
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McCutcheon, F. (författare)
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Medcalf, R. L. (författare)
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(creator_code:org_t)
- 2017-05-16
- 2017
- Engelska.
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:5
- Relaterad länk:
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https://journals.plo...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Rho-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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)
Nyckelord
- acute ischemic-stroke
- focal cerebral-ischemia
- rho-kinase
- intracerebral hemorrhage
- cell
- rock2
- mechanisms
- fasudil
- localization
- thrombolysis
- Science & Technology - Other Topics
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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PLoS ONE
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