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.