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Selective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin

Journal article
Authors B. Niego
N. Lee
Pia Larsson
T. M. de Silva
A. E. L. Au
F. McCutcheon
R. L. Medcalf
Published in PLoS ONE
Volume 12
Issue 5
ISSN 1932-6203
Publication year 2017
Published at Wallenberg Laboratory
Language en
Links doi.org/10.1371/journal.pone.017733...
Keywords acute ischemic-stroke, focal cerebral-ischemia, rho-kinase, intracerebral hemorrhage, cell, rock2, mechanisms, fasudil, localization, thrombolysis, Science & Technology - Other Topics
Subject categories Clinical Medicine

Abstract

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.

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