Nafamostat protects against early brain injury after subarachnoid hemorrhage in mice
Nafamostat protects against early brain injury after subarachnoid hemorrhage in mice
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Nafamostat 可预防小鼠蛛网膜下腔出血后的早期脑损伤
DOI：
10.1016/j.jphs.2021.10.007
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发表时间：
2022
影响因子：
3.5
通讯作者：
Hara Hideaki
中科院分区：
文献类型：
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作者：
Matsubara Hirofumi;Imai Takahiko;Tsuji Shohei;Oka Natsumi;Egashira Yusuke;Enomoto Yukiko;Nakayama Noriyuki;Nakamura Shinsuke;Shimazawa Masamitsu;Iwama Toru;Hara Hideaki
本研究旨在评价奈莫司他（一种丝氨酸蛋白酶抑制剂）在蛛网膜下腔出血（SAH）治疗中的作用。在雄性小鼠中通过血管内穿孔诱导SAH。在SAH诱导后立即腹腔内施用萘莫司他四次。于SAH诱导后24 h进行脑血流量、神经行为学检查、SAH分级及蛋白表达的检测。在体外模型中，人脑微血管内皮细胞（HBMVECs），HBVECs暴露于凝血酶和缺氧24 h，给予萘莫司他，并评估蛋白表达。15只小鼠（17%）因死亡或手术失败而被排除。萘莫司他对SAH分级和脑血流量无明显影响，但可改善神经行为学，抑制凝血酶和MMP-9的表达。另外，体外研究表明，萘莫司他可抑制ICAM-1的表达和p38的磷酸化，对凝血酶和缺氧后的HBMVEC具有保护作用，提示其在改善SAH后神经功能方面的作用。这些发现表明，萘莫司他有可能成为一种新的治疗药物在SAH的管理。
This study aimed to evaluate the effects of nafamostat, a serin protease inhibitor, in the management of subarachnoid hemorrhage (SAH). SAH was induced by endovascular perforation in male mice. Nafamostat was administered intraperitoneally four times immediately after SAH induction. Cerebral blood flow, neurological behavior tests, SAH grade and protein expression were evaluated at 24 h after SAH induction. In thein vitromodel, human brain microvascular endothelial cells (HBMVECs), HBVECs were exposed to thrombin and hypoxia for 24 h; nafamostat was administered and the protein expression was evaluated.Eighty-eight mice were included inthe in vivostudy. Fifteen mice (17%) were excluded because of death or procedure failure. Nafamostat exerted no significant effect on the SAH grade or cerebral blood flow; however, it improved the neurological behavior and suppressed the thrombin and MMP-9 expression. In addition, nafamostat suppressed the ICAM-1 expression and p38 phosphorylation inthe in vitrostudy.Nafamostat has a protective effect against HBMVEC after exposure to thrombin and hypoxia, suggesting its role in improving the neurological outcomes after SAH. These findings indicate that nafamostat has the potential to be a novel therapeutic drug in the management of SAH.