title: Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2.
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 (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). 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. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Morihara
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Syoichiro
authors.initials: S
authors.lastname: Kono
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Shang
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Hishikawa
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Bayer Pharma AG, Drug Discovery-Global Therapeutic Research Groups, Cardiovascular Pharmacology, Wuppertal, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heitmeier
authors.affiliation: Bayer Pharma AG, Drug Discovery-Global Therapeutic Research Groups, Cardiovascular Pharmacology, Wuppertal, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Perzborn
authors.affiliation: Departments of Neurology, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Okayama University, Okayama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D002543:Cerebral Hemorrhage / Q000378:metabolism; D015536:Down-Regulation; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000096:biosynthesis; D044464:Receptor, PAR-2 / Q000096:biosynthesis; D000069552:Rivaroxaban / Q000494:pharmacology*; D020521:Stroke / Q000150:complications; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D014859:Warfarin; D000069552:Rivaroxaban; D010959:Tissue Plasminogen Activator
keywords: PAR-3; PAR-4; tissue plasminogen activator; warfarin