title: Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat.
abstract: This study assesses the risks and benefits of tissue plasminogen activator (tPA) treatment under oral anticoagulation with dabigatran compared with warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO). After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min, followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 hr after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography. Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group compared with the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats. The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partially explain the reduction in hemorrhagic complication by dabigatran reported from clinical study.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Syoichiro
authors.initials: S
authors.lastname: Kono
authors.forename: Kentaro
authors.initials: K
authors.lastname: Deguchi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Omote
authors.forename: Taijun
authors.initials: T
authors.lastname: Yunoki
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurata
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy*; D000069604:Dabigatran; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use; D014859:Warfarin / Q000627:therapeutic use; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D005343:Fibrinolytic Agents; D015091:beta-Alanine; D014859:Warfarin; D010959:Tissue Plasminogen Activator; D000069604:Dabigatran
keywords: dabigatran; hemorrhagic complication; neurovascular unit; pericyte; tPA; thrombolysis