Cai Min, Tong Li, Dong Beibei, Hou Wugang, Shi Likai, Dong Hailong
From the Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China (M.C., L.T., B.D., W.H., L.S., H.D.); and Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing, China (L.T.).
Anesthesiology. 2017 Mar;126(3):507-521. doi: 10.1097/ALN.0000000000001485.
The authors have reported that antioxidative effects play a crucial role in the volatile anesthetic-induced neuroprotection. Accumulated evidence shows that endogenous antioxidation could be up-regulated by nuclear factor-E2-related factor 2 through multiple pathways. However, whether nuclear factor-E2-related factor 2 activation is modulated by sevoflurane preconditioning and, if so, what is the signaling cascade underlying upstream of this activation are still unknown.
Sevoflurane preconditioning in mice was performed with sevoflurane (2.5%) 1 h per day for five consecutive days. Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. Expression of nuclear factor-E2-related factor 2, kelch-like ECH-associated protein 1, manganese superoxide dismutase, thioredoxin-1, and nicotinamide adenine dinucleotide phosphate quinolone oxidoreductase-1 was detected (n = 6). The antioxidant activities and oxidative product expression were also examined. To determine the role of kelch-like ECH-associated protein 1 inhibition-dependent nuclear factor-E2-related factor 2 activation in sevoflurane preconditioning-induced neuroprotection, the kelch-like ECH-associated protein 1-nuclear factor-E2-related factor 2 signal was modulated by nuclear factor-E2-related factor 2 knockout, kelch-like ECH-associated protein 1 overexpression lentivirus, and kelch-like ECH-associated protein 1 deficiency small interfering RNA (n = 8). The infarct volume, neurologic scores, and cellular apoptosis were assessed.
Sevoflurane preconditioning elicited neuroprotection and increased nuclear factor-E2-related factor 2 nuclear translocation, which in turn up-regulated endogenous antioxidation and reduced oxidative injury. Sevoflurane preconditioning reduced kelch-like ECH-associated protein 1 expression. Nuclear factor-E2-related factor 2 ablation abolished neuroprotection and reversed sevoflurane preconditioning by mediating the up-regulation of antioxidants. Kelch-like ECH-associated protein 1 overexpression reversed nuclear factor-E2-related factor 2 up-regulation and abolished the neuroprotection induced by sevoflurane preconditioning. Kelch-like ECH-associated protein 1 small interfering RNA administration improved nuclear factor-E2-related factor 2 expression and the outcome of mice subjected to ischemia/reperfusion injury.
Kelch-like ECH-associated protein 1 down-regulation-dependent nuclear factor-E2-related factor 2 activation underlies the ability of sevoflurane preconditioning to activate the endogenous antioxidant response, which elicits its neuroprotection.
作者曾报道抗氧化作用在挥发性麻醉药诱导的神经保护中起关键作用。越来越多的证据表明，核因子E2相关因子2可通过多种途径上调内源性抗氧化作用。然而，七氟醚预处理是否能调节核因子E2相关因子2的激活，若能调节，该激活上游的信号级联反应是什么，目前仍不清楚。
对小鼠进行七氟醚预处理，每天用2.5%的七氟醚处理1小时，连续处理5天。通过大脑中动脉闭塞诱导局灶性脑缺血/再灌注损伤。检测核因子E2相关因子2、kelch样ECH相关蛋白1、锰超氧化物歧化酶、硫氧还蛋白-1和烟酰胺腺嘌呤二核苷酸磷酸醌氧化还原酶-1的表达（n = 6）。还检测了抗氧化活性和氧化产物表达。为确定kelch样ECH相关蛋白1抑制依赖性核因子E2相关因子2激活在七氟醚预处理诱导的神经保护中的作用，通过核因子E2相关因子2基因敲除、kelch样ECH相关蛋白1过表达慢病毒和kelch样ECH相关蛋白1缺陷小干扰RNA调节kelch样ECH相关蛋白1-核因子E2相关因子2信号（n = 8）。评估梗死体积、神经功能评分和细胞凋亡情况。
七氟醚预处理可诱导神经保护并增加核因子E2相关因子2的核转位，进而上调内源性抗氧化作用并减少氧化损伤。七氟醚预处理降低了kelch样ECH相关蛋白1的表达。核因子E2相关因子2的缺失消除了神经保护作用，并通过介导抗氧化剂的上调逆转了七氟醚预处理的效果。kelch样ECH相关蛋白1的过表达逆转了核因子E2相关因子2的上调，并消除了七氟醚预处理诱导的神经保护作用。给予kelch样ECH相关蛋白1小干扰RNA可改善核因子E2相关因子2的表达以及缺血/再灌注损伤小鼠的预后。
kelch样ECH相关蛋白1下调依赖性核因子E2相关因子2激活是七氟醚预处理激活内源性抗氧化反应并发挥神经保护作用的基础。
