title: Nrf2 activator ameliorates hemorrhagic transformation in focal cerebral ischemia under warfarin anticoagulation.
abstract: OBJECTIVE
  Oxidative stress has been reported to be a main cause of neuronal cell death in ischemia reperfusion injury (IRI). Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important factor involved in anti-oxidative responses. We previously reported that bardoxolone methyl (BARD), an Nrf2 activator, prevented damage induced by IRI. In this study, we investigated the effect of BARD on hemorrhagic transformation in the context of blood brain barrier (BBB) protection.
  
  
  METHODS
  Mice received pre-treatment with warfarin (4.0 mg/kg, p.o.). IRI was subsequently induced 18 h after the warfarin administration by transient middle cerebral artery occlusion (MCAO) for 6 h. BARD (0.06, 0.2, 0.6 or 2.0 mg/kg) or saline was injected intravenously immediately after reperfusion. The infarct volume, neurological score, intracranial hemorrhage volume, and BBB permeability were evaluated 24 h after MCAO. The survival rate and behavioral functional recovery were evaluated for 7 days following IRI. Furthermore, the effects of BARD on BBB components were investigated by western blotting and immunostaining analysis.
  
  
  RESULTS
  BARD suppressed warfarin-mediated increases in the intracranial hemorrhage volume without affecting the infarct volume. BBB permeability was also suppressed by administration of BARD. Western blotting showed that BARD increased expression of BBB components such as endothelial cells, pericytes, and tight junction proteins. Furthermore, immunostaining showed that BARD induced localization of Nrf2 to endothelial cells and pericytes.
  
  
  CONCLUSIONS
  BARD suppressed the exacerbation hemorrhage caused by warfarin pretreatment and ameliorated BBB disruption by protecting endothelial cells, pericytes, and tight junction protein expressions. These results indicate that Nrf2 activators may be an effective therapy against hemorrhagic transformation caused by anticoagulant drugs.
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Takahiko
authors: T
authors: Imai
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan; Department of Neurosurgery, School of Medicine, Gifu University, Gifu 501-1194, Japan.
authors: Toshinori
authors: T
authors: Takagi
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Akira
authors: A
authors: Kitashoji
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan; Department of Neurosurgery, School of Medicine, Gifu University, Gifu 501-1194, Japan.
authors: Keita
authors: K
authors: Yamauchi
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors: Masamitsu
authors: M
authors: Shimazawa
authors: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan. Electronic address: hidehara@gifu-pu.ac.jp.
authors: Hideaki
authors: H
authors: Hara
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D015703:Antigens, CD / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D062725:Tight Junction Proteins / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage*; D000099152:Cadherin 5
chemical_list: D000925:Anticoagulants; D015703:Antigens, CD; D015820:Cadherins; D051267:NF-E2-Related Factor 2; D009828:Oleanolic Acid; D062725:Tight Junction Proteins; D014859:Warfarin; D000099152:Cadherin 5; C495636:Nfe2l2 protein, mouse; C445068:bardoxolone methyl
keywords: BARD; Blood brain barrier; Endothelial cell; Hemorrhagic transformation; Ischemia/reperfusion injury; Nrf2; Pericyte; Warfarin