Protective effects of cilostazol against hemorrhagic stroke: Current and future perspectives

Cilostazol is a phosphodiesterase-3 inhibitor and is known to have pleiotropic effects including antiplatelet and vasodilatation effects and protective effects on endothelial cells. Cilostazol also reportedly reduced stroke recurrence, poststroke intracranial hemorrhage, and extracranial bleeding in a meta-analysis. Although it is known that cilostazol has the potential to suppress hemorrhagic stroke, the precise mechanisms remained unclear. Therefore, we evaluated the protective effects and mechanisms of cilostazol against hemorrhagic stroke. We found that cilostazol prevented the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with intravenous tissue plasminogen activator or warfarin via protecting endothelial cells and tight junction proteins. We also demonstrated that cilostazol attenuated collagenase-induced intracranial hemorrhage in mice. In vitro studies showed that endothelial cells, pericytes, tight junction proteins, adherence junction proteins, and the basement membrane, which are all components of the blood-brain barrier, were protected by the administration of cilostazol following collagenase injury. These results suggested that cilostazol reduces hemorrhagic stroke by protecting the entire blood-brain barrier. Here, we review the protective effects of cilostazol on the blood-brain barrier that result in the prevention of hemorrhagic stroke, discuss the results we obtained using multiple hemorrhagic stroke models, and introduce potential future applications of cilostazol.