Isoflurane Conditioning-Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage-Role of Inducible Nitric Oxide Synthase.
Isoflurane Conditioning-Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage-Role of Inducible Nitric Oxide Synthase.
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DOI：
10.1161/jaha.123.029975
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发表时间：
2023-07-18
影响因子：
5.4
通讯作者：
Athiraman, Umeshkumar
中科院分区：
文献类型：
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作者：
Liu, Meizi;Jayaraman, Keshav;Norris, Aaron J. J.;Hussein, Ahmed;Nelson, James W. W.;Mehla, Jogender;Diwan, Deepti;Vellimana, Ananth;Abu-Amer, Yousef;Zipfel, Gregory J. J.;Athiraman, Umeshkumar
最近的证据表明炎症是动脉瘤性蛛网膜下腔出血（SAH）后迟发性脑缺血的关键驱动因素。诱导型一氧化氮合酶 (iNOS) 是已知的主要炎症介质之一。我们之前表明，吸入麻醉剂异氟烷可以为 SAH 后迟发性脑缺血提供强有力的保护。我们目前的研究旨在确定 iNOS 在异氟烷调理诱导的 SAH 小鼠模型中延迟性脑缺血保护中的作用。实验使用 10 至 14 周龄的雄性野生型 (C57BL/6) 和 iNOS 全局基因敲除小鼠。 SAH 后 1 小时开始使用 2% 异氟烷进行麻醉调理 1 小时。测量了异氟烷诱导的 iNOS 表达变化。 N-(3-(氨基甲基)苄基)乙脒是一种高选择性 iNOS 抑制剂，在 SAH 后立即腹腔注射，然后每天注射。进行血管痉挛、微血管血栓形成和神经系统评估。数据通过单向方差分析和双向重复测量方差分析进行分析，然后进行学生纽曼科伊尔斯比较检验。统计显着性设定为P<0.05。异氟醚调理下调幼稚小鼠和 SAH 小鼠中 iNOS 的表达。 N-(3-(氨基甲基)苄基)乙脒可减轻野生型动物的大动脉血管痉挛和微血管血栓形成并改善神经功能缺损。 iNOS 基因敲除小鼠对 SAH 引起的血管痉挛、微血管血栓形成和神经功能缺损具有显着的抵抗力。将异氟烷与 N-(3-(氨甲基)苯甲基)乙脒结合并不能提供额外的保护，用异氟烷治疗 iNOS 敲除小鼠也没有提供额外的保护。异氟烷调理诱导的延迟性脑缺血保护似乎是通过下调 iNOS 介导的。 iNOS 是改善 SAH 后预后的潜在治疗靶点。
Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning‐induced protection against delayed cerebral ischemia in a mouse model of SAH. The experiments used 10‐ to 14‐week‐old male wild‐type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane‐induced changes in iNOS expression were measured. N‐(3‐(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1‐way ANOVA and 2‐way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P<0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N‐(3‐(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild‐type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N‐(3‐(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Isoflurane conditioning‐induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.