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Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat
Author(s) -
Kono Syoichiro,
Deguchi Kentaro,
Omote Yoshio,
Yunoki Taijun,
Yamashita Toru,
Kurata Tomoko,
Ikeda Yoshio,
Abe Koji
Publication year - 2014
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23302
Subject(s) - dabigatran , neurovascular bundle , medicine , tissue plasminogen activator , stroke (engine) , ischemic stroke , anesthesia , complication , cardiology , ischemia , surgery , atrial fibrillation , warfarin , mechanical engineering , engineering
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. © 2013 Wiley Periodicals, Inc.