The phosphodiesterase III inhibitor cilostazol protects the brain microvasculature from collagenase injury

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Abstract

A patient’s prognosis, including mortality, after intracranial hemorrhage (ICH) is strongly related to the disruption of the blood–brain barrier caused by damage to vascular endothelial cells (ECs). We reported previously that cilostazol, a phosphodiesterase III inhibitor, ameliorated collagenase-induced ICH in a mouse model. We also reported that cilostazol protected cultured ECs in a blood–brain barrier model. However, the influence of cilostazol on vascular structure and cell morphology remains unclear. Therefore, we investigated whether cilostazol exerts protective effects on vascular structures, such as the extracellular matrix (ECM). A mouse model of collagenase-induced ICH was used to observe structures of the brain vasculature in a peri-hemorrhagic lesion using transmission electron microscopy. We then evaluated the morphology of the ECM and cytoskeleton in human brain microvasculature ECs by immunostaining. The brain vasculature was changed 24 h after induction of ICH. Cilostazol (30 mg/kg, orally) suppressed the thinning of the basement membrane, which is formed by the ECM components collagen IV and laminin. Moreover, this drug also suppressed the enlargement of ECs caused by ICH. Collagenase treatment (30 U/ml) of human brain microvasculature ECs caused a decrease in collagen IV expression and an increase in the number and size of the intercellular spaces, as indicated by β-actin immunostaining. Pretreatment of with 10 µM cilostazol suppressed these increases in the number and size of the intercellular spaces. These findings suggest that cilostazol protects the ECM of the brain microvasculature against ICH both in vivo and in vitro.

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