Department of Neurological Surgery, Washington University School of Medicine St. Louis, Missouri, 63108 ; Program in Neuroscience, Washington University School of Medicine St. Louis, Missouri, 63108.
Department of Neurological Surgery, Washington University School of Medicine St. Louis, Missouri, 63108.
Ann Clin Transl Neurol. 2015 Apr;2(4):325-37. doi: 10.1002/acn3.170. Epub 2015 Feb 21.
Outcome after aneurysmal subarachnoid hemorrhage (SAH) depends critically on delayed cerebral ischemia (DCI) - a process driven primarily by vascular events including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction. This study sought to determine the impact of postconditioning - the phenomenon whereby endogenous protection against severe injury is enhanced by subsequent exposure to a mild stressor - on SAH-induced DCI.
Adult male C57BL/6 mice were subjected to sham, SAH, or SAH plus isoflurane postconditioning. Neurological outcome was assessed daily via sensorimotor scoring. Contributors to DCI including cerebral vasospasm, microvessel thrombosis, and microvascular dysfunction were measured 3 days later. Isoflurane-induced changes in hypoxia-inducible factor 1alpha (HIF-1α)-dependent genes were assessed via quantitative polymerase chain reaction. HIF-1α was inhibited pharmacologically via 2-methoxyestradiol (2ME2) or genetically via endothelial cell HIF-1α-null mice (EC-HIF-1α-null). All experiments were performed in a randomized and blinded fashion.
Isoflurane postconditioning initiated at clinically relevant time points after SAH significantly reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type (WT) mice. Isoflurane modulated HIF-1α-dependent genes - changes that were abolished in 2ME2-treated WT mice and EC-HIF-1α-null mice. Isoflurane-induced DCI protection was attenuated in 2ME2-treated WT mice and EC-HIF-1α-null mice.
Isoflurane postconditioning provides strong HIF-1α-mediated macro- and microvascular protection in SAH, leading to improved neurological outcome. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for SAH.
动脉瘤性蛛网膜下腔出血（SAH）的预后取决于迟发性脑缺血（DCI）——这一过程主要由血管事件驱动，包括脑血管痉挛、微血管血栓形成和微血管功能障碍。本研究旨在确定后处理——即通过随后暴露于轻度应激源来增强对内源性严重损伤的保护——对 SAH 诱导的 DCI 的影响。
成年雄性 C57BL/6 小鼠接受假手术、SAH 或 SAH 加异氟烷后处理。通过传感器运动评分每天评估神经功能预后。3 天后测量 DCI 的促成因素，包括脑血管痉挛、微血管血栓形成和微血管功能障碍。通过定量聚合酶链反应评估异氟烷诱导的缺氧诱导因子 1α（HIF-1α）依赖性基因的变化。通过 2-甲氧基雌二醇（2ME2）或内皮细胞 HIF-1α 缺失小鼠（EC-HIF-1α-null）进行药理学抑制 HIF-1α。所有实验均以随机和盲法进行。
在 SAH 后临床相关时间点开始的异氟烷后处理显著降低了野生型（WT）小鼠的脑血管痉挛、微血管血栓形成、微血管功能障碍和神经功能缺损。异氟烷调节 HIF-1α 依赖性基因——这些变化在 2ME2 处理的 WT 小鼠和 EC-HIF-1α 缺失小鼠中被消除。在 2ME2 处理的 WT 小鼠和 EC-HIF-1α 缺失小鼠中，异氟烷诱导的 DCI 保护作用减弱。
异氟烷后处理在 SAH 中提供强烈的 HIF-1α 介导的宏观和微观血管保护，导致神经功能预后改善。这些结果表明脑血管是异氟烷后处理提供的脑保护的关键靶点，HIF-1α 是这种血管保护的关键介质。它们还确定异氟烷后处理是一种有前途的新型 SAH 治疗方法。
