title: Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
abstract: The purpose of the present study was to investigate whether cilostazol, a phosphodiesterase-III inhibitor and antiplatelet drug, would prevent tPA-associated hemorrhagic transformation. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone at 6 h, with combined tPA plus cilostazol at 6 h, or with vehicle at 6 h. We used multiple imaging (electron microscopy, spectroscopy), histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To further investigate the mechanism of cilostazol to beneficial effect, we also performed an in vitro study with tPA and a phosphodiesterase-III inhibitor in human brain microvascular endothelial cells, pericytes, and astrocytes. Combination therapy with tPA plus cilostazol prevented development of hemorrhagic transformation, reduced brain edema, prevented endothelial injury via reduction MMP-9 activity, and prevented the blood-brain barrier opening by inhibiting decreased claudin-5 expression. These changes significantly reduced the morbidity and mortality at 18 h and 7 days after the reperfusion. Also, the administration of both drugs prevented injury to brain human endothelial cells and human brain pericytes. The present study indicates that a phosphodiesterase-III inhibitor prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mishiro
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Huayue
authors.initials: H
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Izuta
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Masahiko
authors.initials: M
authors.lastname: Satoh
authors.forename: Toru
authors.initials: T
authors.lastname: Iwama
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000473:pathology*; D000077407:Cilostazol; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry*; D006470:Hemorrhage / Q000188:drug therapy*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008833:Microcirculation; D008854:Microscopy, Electron / Q000379:methods; D020286:Pericytes / Q000166:cytology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D000077407:Cilostazol