Beneficial Properties of Argon After Experimental Subarachnoid Hemorrhage: Early Treatment Reduces Mortality and Influences Hippocampal Protein Expression
Beneficial Properties of Argon After Experimental Subarachnoid Hemorrhage: Early Treatment Reduces Mortality and Influences Hippocampal Protein Expression
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DOI：
10.1097/ccm.0000000000001561
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发表时间：
2016-07-01
影响因子：
8.8
通讯作者：
Coburn, Mark
中科院分区：
文献类型：
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作者：
Hoellig, Anke;Weinandy, Agnieszka;Coburn, Mark
目的：到目前为止，改善蛛网膜下腔出血后早期脑损伤的治疗还不存在。在这里，我们评估氩气在实验性蛛网膜下腔出血后的神经保护特性，以死亡率为主要终点和功能结局，海马细胞和分子应激反应为次要终点。设计：随机对照动物研究。环境：大学研究实验室。实验对象：雄性Sprague-Dawley大鼠98只。干预措施：经血管内穿孔技术或假手术诱导蛛网膜下腔出血1小时后，给予含有50 vol%氩气/50 vol%氧气（氩气组）或50 vol%氮气/50 vol%氧气（对照组）的混合呼吸气体1小时。测量方法和主要结果：主要目的是观察蛛网膜下腔出血后的死亡率。此外，通过1)神经学测试和2)蛛网膜下腔出血后24小时的开放野试验来评估结果，3)海马样本缺氧诱导因子1 α和血红素加氧酶1的蛋白分析，以及4)海马切片的免疫组织化学来量化重要神经元。动物在蛛网膜下腔出血或假手术后6、24或72小时被安乐死。评估过早死亡（预定安乐死前死亡）的发生情况。与对照组相比，氩气后处理导致过早死亡的风险降低至20.6% （95% CI, 4.39-96.7）。氩气组的体重在整个观察期内均高于对照组（p < 0.05）。两组神经评分无差异（p = 0.550）。氩组海马缺氧诱导因子1 α和血红素加氧酶1的表达增加。氩气组大鼠蛛网膜下腔出血后24小时海马内重要神经元数量增加。结论：实验性蛛网膜下腔出血后应用氩气达到降低死亡风险的主要目的。此外，在整个观察期内，氩气组的体重较高，表明整体状况良好。从作用机制上看，缺氧诱导因子1 α诱导血红素加氧酶1表达提高神经元存活率可能是蛛网膜下腔出血后氩气应用的有益作用机制之一。
Objectives: Until now, treatment ameliorating early brain injury following subarachnoid hemorrhage has been nonexistent. Here, we evaluate the neuroprotective properties of argon after experimental subarachnoid hemorrhage with mortality as the primary endpoint and functional outcome, as well as hippocampal cellular and molecular stress response as secondary endpoints.Design: Randomized controlled animal study.Setting: University research laboratory.Subjects: Ninety-eight male Sprague-Dawley rats.Interventions: One hour after subarachnoid hemorrhage induction via endovascular perforation technique or sham surgery, a breathing gas mixture containing 50 vol% argon/50 vol% oxygen (argon group) or 50 vol% nitrogen/50 vol% oxygen (control group) was applied for 1 hour.Measurements and Main Results: The primary objective was mortality after subarachnoid hemorrhage. Additionally, outcome was assessed via 1) neurologic testing and 2) an open-field test 24 hours after subarachnoid hemorrhage, 3) protein analysis of hippocampal samples for hypoxia-inducible factor 1 alpha and heme oxygenase 1, and 4) immunohistochemistry of hippocampal slices to quantify vital neurons. Animals were euthanized 6, 24, or 72 hours after subarachnoid hemorrhage or sham surgery. Occurrence of premature death (death prior to scheduled euthanasia) was assessed. Postconditioning with argon resulted in a reduction of risk with respect to premature death to 20.6% compared with the control group (95% CI, 4.39-96.7). Body weight was higher in the argon group over the entire observation period (p < 0.05). There was no difference in the neuroscore (p = 0.550). Expression of hypoxia-inducible factor 1 alpha and heme oxygenase 1 in the hippocampus was increased in the argon group. Higher quantity of vital neurons in the hippocampal samples of the argon group was discovered 24 hours after subarachnoid hemorrhage.Conclusions: Argon application after experimental subarachnoid hemorrhage met the primary endpoint of reducing the risk of mortality. In addition, higher body weight indicating good overall condition was observed in the argon group over the entire observation period. Regarding the mechanism of action, hypoxia-inducible factor 1 alpha-induced heme oxygenase 1 expression resulting in improved survival of neurons may contribute to the beneficial effect of argon application after subarachnoid hemorrhage.