Early initiation of a factor Xa inhibitor can attenuate tissue repair and neurorestoration after middle cerebral artery occlusion
Early initiation of a factor Xa inhibitor can attenuate tissue repair and neurorestoration after middle cerebral artery occlusion
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早期开始使用 Xa 因子抑制剂可减弱大脑中动脉闭塞后的组织修复和神经恢复
DOI：
10.1016/j.brainres.2019.05.020
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发表时间：
2019
期刊：
影响因子：
2.9
通讯作者：
Kitazono Takanari
中科院分区：
文献类型：
--
作者：
Komori Motohiro;Ago Tetsuro;Wakisaka Yoshinobu;Nakamura Kuniyuki;Tachibana Masaki;Yoshikawa Yoji;Shibahara Tomoya;Yamanaka Kei;Kuroda Junya;Kitazono Takanari
急性心源性卒中后开始抗凝治疗的时机仍有争议。我们研究了中风后给予Xa因子抑制剂对小鼠的影响，重点是组织修复和功能恢复的结果。我们在CB-17小鼠永久性远端大脑中动脉闭塞（pMCAO）后立即开始给予利伐沙班（一种Xa抑制剂），这些小鼠在基线时几乎没有软脑膜炎。在pMCAO后立即开始利伐沙班通过抑制软脑膜吻合发展阻碍了缺血区域的血流恢复，并导致神经功能恢复受损，伴较不广泛的梗死周围星形胶质细胞增生。在梗死区域内，利伐沙班喂养小鼠的血管生成和纤维化反应减弱。此外，在pMCAO后立即用利伐沙班治疗的小鼠中，梗死区域中的炎症反应，包括嗜中性粒细胞和单核细胞/巨噬细胞的积聚、促炎细胞因子的局部分泌和血脑屏障的破坏，均得到增强。在短暂性MCAO后或pMCAO后第7天开始利伐沙班时，未发现有害作用。总的来说，卒中后早期开始Xa因子抑制剂治疗可能会抑制缺血区域的软脑膜吻合发展和血流恢复，从而导致组织修复和功能恢复减弱，除非闭塞的大动脉成功再通。
The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO) in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood–brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized.