Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain

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• 作者：Jingwei Shang ; PhD ; Toru Yamashita ; PhD ; Syoichiro Kono ; PhD ; Ryuta Morihara ; PhD ; Yumiko Nakano ; PhD ; Yusuke Fukui ; Xianghong Li ; PhD ; Nozomi Hishikawa ; PhD ; Yasuyuki Ohta ; PhD ; Koji Abe ; PhD ; ^{shangjw2@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ischemia ; neurovascular unit dissociation ; rivaroxaban ; thrombolysis ; warfarin
• 刊名：Journal of Stroke and Cerebrovascular Diseases
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：25
• 期：8
• 页码：1997-2003
• 全文大小：1477 K

文摘

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.