title: Cilostazol ameliorates collagenase-induced cerebral hemorrhage by protecting the blood-brain barrier.
abstract: Intracranial hemorrhage remains a devastating disease. Among antiplatelet drugs, cilostazol, a phosphodiesterase 3 inhibitor, was recently reported to prevent secondary hemorrhagic stroke in patients in a clinical trial. The aim of this study was to evaluate whether pre-treatment with cilostazol could decrease the intracranial hemorrhage volume and examine the protective mechanisms of cilostazol. We evaluated the pre-treatment effects of the antiplatelet drug cilostazol on the collagenase-induced intracranial hemorrhage volume and neurological outcomes in mice. To estimate the mechanism of collagenase injury, we evaluated various vascular components in vitro, including endothelial cells, vascular smooth muscle cells, pericytes, and a blood-brain barrier model. Cilostazol pre-treatment reduced the intracranial hemorrhage volume with sufficient inhibition of platelet aggregation, and motor function was improved by cilostazol treatment. Blood-brain barrier permeability was increased by collagenase-induced intracranial hemorrhage, and cilostazol attenuated blood-brain barrier leakage. Terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot analysis showed that cilostazol prevented pericyte cell death by inducing cyclic adenosine monophosphate-responsive element-binding protein phosphorylation. Cilostazol also prevented endothelial cell death and protected collagen type 4, laminin, and vascular endothelial- and N-cadherins from collagenase injury. In conclusion, cilostazol reduced collagenase-induced intracranial hemorrhage volume by protecting the blood-brain barrier.
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.|Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Imai
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mishiro
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Ishisaka
authors.affiliation: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.|Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tsujimoto
authors.affiliation: First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Matsukawa
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.affiliation: Department of Neurosurgery, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshimura
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
authors.affiliation: Department of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Iwama
authors.affiliation: Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu, Japan hidehara@gifu-pu.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D000077407:Cilostazol; D017364:Collagenases; D042783:Endothelial Cells / Q000187:drug effects; D051379:Mice; D020286:Pericytes / Q000166:cytology; D011292:Premedication / Q000379:methods; D020011:Protective Agents; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D020011:Protective Agents; D013777:Tetrazoles; D017364:Collagenases; D000077407:Cilostazol
keywords: Cilostazol; blood–brain barrier; collagenase; intracranial hemorrhage; pericyte