Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat

Syoichiro Kono, Kentaro Deguchi, Yoshio Omote, Taijun Yunoki, Toru Yamashita, Tomoko Kurata, Yoshio Ikeda, Koji Abe

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)46-53
Number of pages8
JournalJournal of Neuroscience Research
Volume92
Issue number1
DOIs
Publication statusPublished - Jan 2014

Fingerprint

Tissue Plasminogen Activator
Warfarin
Stroke
Pericytes
Middle Cerebral Artery Infarction
Cerebral Hemorrhage
Matrix Metalloproteinases
Reperfusion
Paraparesis
Carboxymethylcellulose Sodium
Cerebral Infarction
Brain
Blood Coagulation
Dabigatran
Basement Membrane
Astrocytes
Salts
Sodium

Keywords

  • Dabigatran
  • Hemorrhagic complication
  • Neurovascular unit
  • Pericyte
  • Thrombolysis
  • TPA

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat. / Kono, Syoichiro; Deguchi, Kentaro; Omote, Yoshio; Yunoki, Taijun; Yamashita, Toru; Kurata, Tomoko; Ikeda, Yoshio; Abe, Koji.

In: Journal of Neuroscience Research, Vol. 92, No. 1, 01.2014, p. 46-53.

Research output: Contribution to journalArticle

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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.",
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