Rivaroxaban Reduces Cerebral Hemorrhage in Mice with TPA Ischemic Stroke after Thrombolysis by Down-Regulating PAR-1 and PAR-2
Rivaroxaban Reduces Cerebral Hemorrhage in Mice with TPA Ischemic Stroke after Thrombolysis by Down-Regulating PAR-1 and PAR-2
Sen Ye1, Jiangang Pang2 and Xiuli Wang3*
ABSTRACT
The objective of this study was to investigate the mechanism by which rivaroxaban reduces cerebral hemorrhage in mice with TPA ischemic stroke after thrombolysis. Male Wistar mice (11-week-old) as our experimental subjects were administered with warfarin (0.2 mg/kg/day), rivaroxaban (60 mg/kg/day), rivaroxaban (120 mg/kg) /day), or solvent pretreatment for 14 d to induce transient middle cerebral artery occlusion for 90 min, followed by perfusion with tPA (10 mg/kg/10ml). Infarct volume, bleeding volume, immunoglobulin G leakage and blood parameters were examined. PAR immunohistochemistry was performed on brain sections after 24 h reperfusion. We found that compared with the rivaroxaban group, the warfarin pretreatment group had an increased ICH volume; PAR-1, -2, -3, and -4 were widely expressed in the normal brain and there was higher expression in the ischemic brain, especially in ischemic peripheral lesions. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in preischemic and post-ischemic lesions, whereas rivaroxaban pretreatment had no such effect. This study suggests that rivaroxaban pretreatment causes lower risk of cerebral hemorrhage in mice than warfarin pretreatment. we conclude that, compared with warfarin pretreatment, the relative down-regulation of PAR-1 and PAR-2 in rivaroxaban pretreatment may be involved in the mechanism of reduction in bleeding complications.
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