12/15-Lipoxygenase Inhibition or Knockout Reduces Warfarin-Associated Hemorrhagic Transformation After Experimental Stroke by Yu Liu, Yi Zheng, Hulya Karatas,

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12/15-Lipoxygenase Inhibition or Knockout Reduces Warfarin-Associated Hemorrhagic Transformation After Experimental Stroke by Yu Liu, Yi Zheng, Hulya Karatas, Xiaoying Wang, Christian Foerch, Eng H. Lo, and Klaus van Leyen Stroke Volume 48(2):445-451 January 23, 2017 Copyright © American Heart Association, Inc. All rights reserved.

A, Increasing amounts of warfarin added to the drinking water of mice led to increased international normalized ratio (INR) values 24 h later (**P<0.01, ***P<0.001 compared with no added warfarin; n=6 per group). A, Increasing amounts of warfarin added to the drinking water of mice led to increased international normalized ratio (INR) values 24 h later (**P<0.01, ***P<0.001 compared with no added warfarin; n=6 per group). B, Experimental setup with 24 h warfarin preadministration, followed by either 3 h of MCAO (experiment A) or 2 h of MCAO, followed by tissue-type plasminogen activator (tPA) treatment 1 h after reperfusion (experiment B). Timeline not to scale. C, Photometrically determined hemoglobin levels in the ipsilateral brain hemisphere after warfarin pretreatment and 3 h of middle cerebral artery occlusion (MCAO) were significantly lower in 12/15-lipoxygenase (12/15-LOX) knockout mice compared with matching wild-type mice (*P<0.05; n=5 per group). Expt indicates experiment. Yu Liu et al. Stroke. 2017;48:445-451 Copyright © American Heart Association, Inc. All rights reserved.

A, Significantly reduced hemoglobin levels in C57Bl6 mice treated with the 12/15-lipoxygenase (12/15-LOX) inhibitor ML351 after warfarin and 3 h of middle cerebral artery occlusion (MCAO), compared with vehicle treatment (**P<0.01). A, Significantly reduced hemoglobin levels in C57Bl6 mice treated with the 12/15-lipoxygenase (12/15-LOX) inhibitor ML351 after warfarin and 3 h of middle cerebral artery occlusion (MCAO), compared with vehicle treatment (**P<0.01). B, Less hemorrhage was detected in brain sections of mice treated with ML351 (**P<0.01). C, Infarct size comparison after triphenyltetrazolium hydrochloride staining in mice subjected to warfarin plus 3 h of MCAO showed large infarcts in the vehicle-treated mice, which were slightly but significantly reduced after ML351 treatment (*P<0.05). D, After normalization for infarct size, hemorrhage remained significantly reduced by ML351 treatment (*P<0.05). tPA indicates tissue-type plasminogen activator. Yu Liu et al. Stroke. 2017;48:445-451 Copyright © American Heart Association, Inc. All rights reserved.

A, After warfarin pretreatment, then 2 h of middle cerebral artery occlusion (MCAO), and tissue-type plasminogen activator (tPA) infusion 1 h later, IP ML351 delivered concomitantly reduced hemoglobin levels in the ipsilateral side of the brain at 24 h (*P<0.05). A, After warfarin pretreatment, then 2 h of middle cerebral artery occlusion (MCAO), and tissue-type plasminogen activator (tPA) infusion 1 h later, IP ML351 delivered concomitantly reduced hemoglobin levels in the ipsilateral side of the brain at 24 h (*P<0.05). B, Hemorrhage in brain sections was significantly reduced by treatment with ML351 (*P<0.05; n=5 for vehicle, n=7 for ML351). C, 12/15-lipoxygenase (12/15-LOX) protein, detected by immunohistochemistry, was increased in the brains of warfarin-pretreated mice (***P<0.001, *P<0.05 compared with MCAO only; n=3 per group, 24 images per brain) after MCAO. D, Representative images show that most of the increased 12/15-LOX signal after warfarin treatment is vessel derived (scale bar=100 µm). W, warfarin. Yu Liu et al. Stroke. 2017;48:445-451 Copyright © American Heart Association, Inc. All rights reserved.

A, Seven days after warfarin plus 2 h of middle cerebral artery occlusion (MCAO) treatment, survival was better in ML351-treated animals, but the difference was not statistically significant (P=0.24; n=7 per group). A, Seven days after warfarin plus 2 h of middle cerebral artery occlusion (MCAO) treatment, survival was better in ML351-treated animals, but the difference was not statistically significant (P=0.24; n=7 per group). B, Behavioral outcome was significantly improved in the ML351 treatment group (P<0.05 by 2-way ANOVA). Yu Liu et al. Stroke. 2017;48:445-451 Copyright © American Heart Association, Inc. All rights reserved.