title: 12/15-Lipoxygenase Inhibition or Knockout Reduces Warfarin-Associated Hemorrhagic Transformation After Experimental Stroke.
abstract: For stroke prevention, patients with atrial fibrillation typically receive oral anticoagulation. The commonly used anticoagulant warfarin increases the risk of hemorrhagic transformation (HT) when a stroke occurs; tissue-type plasminogen activator treatment is therefore restricted in these patients. This study was designed to test the hypothesis that 12/15-lipoxygenase (12/15-LOX) inhibition would reduce HT in warfarin-treated mice subjected to experimental stroke.
  
  
  
  Warfarin was dosed orally in drinking water, and international normalized ratio values were determined using a Coaguchek device. C57BL6J mice or 12/15-LOX knockout mice were subjected to transient middle cerebral artery occlusion with 3 hours severe ischemia (model A) or 2 hours ischemia and tissue-type plasminogen activator infusion (model B), with or without the 12/15-LOX inhibitor ML351. Hemoglobin was determined in brain homogenates, and hemorrhage areas on the brain surface and in brain sections were measured. 12/15-LOX expression was detected by immunohistochemistry.
  
  
  
  Warfarin treatment resulted in reproducible increased international normalized ratio values and significant HT in both models. 12/15-LOX knockout mice suffered less HT after severe ischemia, and ML351 reduced HT in wild-type mice. When normalized to infarct size, ML351 still independently reduced hemorrhage. HT after tissue-type plasminogen activator was similarly reduced by ML351.
  
  
  
  In addition to its benefits in infarct size reduction, 12/15-LOX inhibition also may independently reduce HT in warfarin-treated mice. ML351 should be further evaluated as stroke treatment in anticoagulated patients suffering a stroke, either alone or in conjunction with tissue-type plasminogen activator.
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.).|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.).|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.).|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Hulya
authors.initials: H
authors.lastname: Karatas
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.).|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.).|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.).|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: From the Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown (Y.L., Y.Z., H.K., X.W., E.H.L., K.v.L.); Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, China (Y.L.); and Department of Neurology, Goethe University, Frankfurt am Main, Germany (C.F.). klaus_vanleyen@hms.harvard.edu.|Dr Karatas: Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey. klaus_vanleyen@hms.harvard.edu.
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency* / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency* / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology*; D014859:Warfarin / Q000633:toxicity*
chemical_list: C475064:12-15-lipoxygenase; D000925:Anticoagulants; D004791:Enzyme Inhibitors; D014859:Warfarin; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: atrial fibrillation; brain; hemorrhage; stroke; warfarin