Hemorrhagic stroke occurs when a weakened vessel
ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of
hemorrhagic stroke, and no
therapies have proven effective to prevent
hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for
hemorrhagic stroke. ROCKs, which belong to the
serine/threonine protein kinase family and participate in the organization of actin cytoskeleton, have become attractive targets for the treatment of
strokes. In this study, in vitro
enzyme-based assays revealed that a new compound (FPND) with a novel scaffold identified by docking-based virtual screening could inhibit ROCK1 specifically at low micromolar concentration. Molecular modeling showed that FPND preferentially interacted with ROCK1, and the difference between the binding affinity of FPND toward ROCK1 and ROCK2 primarily resulted from non-polar contributions. Furthermore, FPND significantly prevented
statin-induced
cerebral hemorrhage in a zebrafish model. In addition, in vitro studies using the xCELLigence RTCA system, immunofluorescence and western blotting revealed that FPND prevented
statin-induced
cerebral hemorrhage by enhancing endothelial cell-cell junctions through inhibiting the ROCK-mediated
VE-cadherin signaling pathway. As indicated by the extremely low toxicity of FPND against mice, it is safe and can potentially prevent vascular integrity loss-related diseases, such as
hemorrhagic stroke.