title: Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia.
abstract: OBJECTIVE
  The Cilostazol Stroke Prevention Study II has shown a similar efficacy in stroke prevention but markedly fewer hemorrhagic events with the phosphodiesterase inhibitor cilostazol versus aspirin. The purpose of this study is therefore to investigate how cilostazol affects cerebral hemodynamics and whether it prevents hemorrhagic transformation induced by recombinant tissue plasminogen activator (rtPA) in a mouse model of focal ischemia/reperfusion. Particular emphasis will be placed on the plasma-microvessel interface.
  
  
  METHODS
  After receiving food containing 0.3% cilostazol or standard food for 7 days, adult C57BL/6J mice were subjected to middle cerebral artery occlusion/reperfusion with or without rtPA (10mg/kg) intravenously administered prior to reperfusion. Cerebral blood flow was monitored at several time points by laser speckle imaging in the 24 hour period post reperfusion, before neurobehavioral and histological assessment. The long-term effect of cilostazol on cerebral ischemia was analyzed in the non-rtPA cohort.
  
  
  RESULTS
  In the non-rtPA cohort, pretreatment by cilostazol significantly decreased the endothelial expression of adhesion molecules (P-selectin and intercellular adhesion molecule-1) and prevented platelet aggregation and leukocyte plugging in the microvessels after cerebral ischemia/reperfusion in the acute phase. Cilostazol significantly reduced mortality rate and improved motor function at 7 days post-ischemia/reperfusion. In the rtPA cohort, cilostazol significantly suppressed edema formation and hemorrhagic transformation with reduced density of microglial cells positive for matrix metalloproteinase-9 in the cerebral cortex and the striatum. In both cohorts, cilostazol significantly suppressed focal no-reflow, mitigated cerebral infarct, and improved neurological outcome.
  
  
  CONCLUSIONS
  Cilostazol may possess protective properties against cerebral ischemic injury by preventing no-reflow and hemorrhagic transformation, via maintenance of microvascular integrity.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan. hasecchi@kuhp.kyoto-u.ac.jp
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hase
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Youshi
authors.initials: Y
authors.lastname: Fujita
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitamura
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakabayashi
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Washida
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D000077407:Cilostazol; D003911:Dextrans; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D006470:Hemorrhage / Q000517:prevention & control*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D017078:Laser-Doppler Flowmetry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D015424:Reperfusion; D018709:Statistics, Nonparametric; D013777:Tetrazoles / Q000008:administration & dosage*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000009:adverse effects
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D003911:Dextrans; D008840:Microfilament Proteins; D010726:Phosphodiesterase Inhibitors; D013777:Tetrazoles; C015219:fluorescein isothiocyanate dextran; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; D016650:Fluorescein-5-isothiocyanate; D000077407:Cilostazol