Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR‐1 and PAR‐2. Issue 9 (30th December 2016)

• Record Type: Journal Article
• Authors: Morihara, Ryuta; Yamashita, Toru; Kono, Syoichiro; Shang, Jingwei; Nakano, Yumiko; Sato, Kota; Hishikawa, Nozomi; Ohta, Yasuyuki; Heitmeier, Stefan; Perzborn, Elisabeth; Abe, Koji
• Is Part Of: Journal of neuroscience research. Volume 95:Issue 9(2017)
• Page Start: 1818
• Page End: 1828
• Publication Date: 2016-12-30
• Subjects: PAR‐3 -- PAR‐4 -- tissue plasminogen activator -- warfarin; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.24013
• Languages: English
• ISSNs: 0360-4012

Abstract

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. Abstract : In an animal stroke model followed by tissue‐type plasminogen activator (tPA), we observed that warfarin pretreatment (W+tPA) enhanced the expression of protease‐activated receptor‐1 (PAR‐1) in the brain compared with the vehicle group (V+tPA), whereas rivaroxaban pretreatment (R+tPA) did not.