TY  - JOUR
AU  - Niego, B
AU  - Lee, N
AU  - Larsson, P
AU  - de Silva, TM
AU  - Au, AE-L
AU  - McCutcheon, F
AU  - Medcalf, RL
Y2  - 2021/02/04
Y1  - 2017/05/16
SN  - 1932-6203
UR  - http://hdl.handle.net/11343/259429
AB  - 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.
LA  - English
PB  - PUBLIC LIBRARY SCIENCE
T1  - Selective inhibition of brain endothelial Rhokinase-2 provides optimal protection of an in vitro blood-brain barrier from tissue-type plasminogen activator and plasmin
DO  - 10.1371/journal.pone.0177332
IS  - PLoS One
VL  - 12
IS  - 5
L1  - /bitstream/handle/11343/259429/PMC5433693.pdf?sequence=1&isAllowed=y
ER  -