Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2

Ryuta Morihara, Toru Yamashita, Syoichiro Kono, Jingwei Shang, Yumiko Nakano, Kota Sato, Nozomi Hishikawa, Yasuyuki Ohta, Stefan Heitmeier, Elisabeth Perzborn, Koji Abe

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Abstract

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2mg/kg/day), low-dose rivaroxaban (60mg/kg/day), high-dose rivaroxaban (120mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90min, followed by reperfusion with tPA (10mg/kg/10ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials.

Original languageEnglish
JournalJournal of Neuroscience Research
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

Plasminogen Activators
Cerebral Hemorrhage
Warfarin
Down-Regulation
Brain
Reperfusion
PAR-2 Receptor
PAR-1 Receptor
Rivaroxaban
Intracranial Hemorrhages
Middle Cerebral Artery Infarction
Tissue Plasminogen Activator
Brain Ischemia
Wistar Rats
Immunoglobulin G
Immunohistochemistry
Clinical Trials

Keywords

  • PAR-3
  • PAR-4
  • Tissue plasminogen activator
  • Warfarin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2. / Morihara, Ryuta; Yamashita, Toru; Kono, Syoichiro; Shang, Jingwei; Nakano, Yumiko; Sato, Kota; Hishikawa, Nozomi; Ohta, Yasuyuki; Heitmeier, Stefan; Perzborn, Elisabeth; Abe, Koji.

In: Journal of Neuroscience Research, 2016.

Research output: Contribution to journalArticle

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abstract = "This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2mg/kg/day), low-dose rivaroxaban (60mg/kg/day), high-dose rivaroxaban (120mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90min, followed by reperfusion with tPA (10mg/kg/10ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials.",
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AU - Morihara, Ryuta

AU - Yamashita, Toru

AU - Kono, Syoichiro

AU - Shang, Jingwei

AU - Nakano, Yumiko

AU - Sato, Kota

AU - Hishikawa, Nozomi

AU - Ohta, Yasuyuki

AU - Heitmeier, Stefan

AU - Perzborn, Elisabeth

AU - Abe, Koji

PY - 2016

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AB - This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2mg/kg/day), low-dose rivaroxaban (60mg/kg/day), high-dose rivaroxaban (120mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90min, followed by reperfusion with tPA (10mg/kg/10ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials.

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