Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, USA.
Department of Neurological Surgery, Washington University in Saint Louis, Saint Louis, MO 63110, USA.
Int J Mol Sci. 2021 Apr 20;22(8):4291. doi: 10.3390/ijms22084291.
We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.
我们最近报道了异氟醚预处理通过上调内皮型一氧化氮合酶（eNOS）提供了多方面的蛛网膜下腔出血（SAH）后迟发性脑缺血（DCI）的保护作用，SIRT1 是 eNOS 的关键调节因子之一。我们目前的研究目的是研究 SIRT1 在异氟醚预处理诱导的神经血管保护作用中对 SAH 诱导的 DCI 的作用。将小鼠分为四组：假手术组、SAH 组、SAH 后给予异氟醚预处理组（预处理组）和异氟醚预处理加 EX-527 组（预处理+EX-527 组）。通过血管内穿孔进行实验性 SAH。SAH 后 1 小时给予异氟醚 2%麻醉预处理 1 小时。SAH 后立即在 EX-527 组中腹腔注射选择性 SIRT1 抑制剂 EX-527（10mg/kg）。测量 SIRT1mRNA 表达和活性水平。评估血管痉挛、微血管血栓形成和神经功能结局。异氟醚暴露后 SIRT1mRNA 表达下调，SIRT1 活性无差异。无论是否给予 EX-527，异氟醚预处理均减轻血管痉挛、微血管血栓形成和改善神经功能结局。我们的数据验证了我们之前的发现，即异氟醚预处理对 SAH 引起的宏观和微观血管缺陷提供了强大的保护作用，但这种保护可能不是通过 SIRT1 途径介导的。
