title: Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain.
abstract: BACKGROUND
  Warfarin and rivaroxaban are highly effective in reducing stroke risk in patients with atrial fibrillation (AF). However, their effects on anticoagulation and neurovascular unit (NVU) change remain elusive. In this study, we assessed the risks and benefits of pre-treatment with warfarin or rivaroxaban after tissue-type plasminogen activator (tPA) thrombolysis in ischemic rat brain.
  
  
  METHODS
  Pre-treatment with warfarin (.2 mg/kg/day), low dose rivaroxaban (60 mg/kg/day), high dose rivaroxaban (120 mg/kg/day) or vehicle was performed for 2 weeks, transient middle cerebral artery occlusion (tMCAO) was induced for 90 min, then followed by reperfusion with tPA. At 24 hours (h) after reperfusion, we observed the changes of matrix metalloproteinase-9 (MMP-9), tissue factor, caspase 3 and NVU dissociation.
  
  
  RESULTS
  Prothrombin time (PT) was significantly prolonged in the warfarin and rivaroxaban pretreated groups. MMP-9 expression greatly increased in the warfarin group, and this was reduced in the rivaroxaban groups compared with the vehicle group. Tissue factor expression remarkably decreased in the warfarin and rivaroxaban groups. The number of caspase 3-positive cells had no difference among all the groups. Marked dissociations between astrocyte foot processes and the basal lamina or pericytes were observed in the warfarin pretreated group, but such dissociations were improved in the rivaroxaban groups.
  
  
  CONCLUSIONS
  Our present study shows that pre-treatment with rivaroxaban was noninferior to warfarin in the anticoagulation, but a lower risk of NVU dysfunction and dissociation after tPA treatment in rivaroxaban. This finding could partly explain the mechanism of reducing hemorrhagic complications by rivaroxaban in clinical studies.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Syoichiro
authors.initials: S
authors.lastname: Kono
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Morihara
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fukui
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Hishikawa
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address: shangjw2@gmail.com.
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D037121:Plant Lectins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D000069552:Rivaroxaban / Q000008:administration & dosage*; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D005904:Glial Fibrillary Acidic Protein; D037121:Plant Lectins; C034981:tomato lectin; D014859:Warfarin; D003094:Collagen; D000069552:Rivaroxaban; D017479:Receptors, Platelet-Derived Growth Factor; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9
keywords: Ischemia; neurovascular unit dissociation; rivaroxaban; thrombolysis; warfarin