Li Chang, Wu Ziyi, Xue Hang, Gao Qiushi, Kuai Shihui, Zhao Ping
From the Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
Anesth Analg. 2025 May 16;141(3):648-59. doi: 10.1213/ANE.0000000000007547.
The mechanisms by which sevoflurane protects the brain from hypoxic-ischemic brain injury (HIBI) are unknown. Ferroptosis occurs during HIBI and is regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2). This study investigated the roles of Nrf2-regulated ferroptosis in sevoflurane postconditioning (SPC)-mediated neuroprotection during HIBI.
HIBI was induced in 7-day-old rats. SPC (2.5%, 30 minutes) was performed immediately after HIBI, and some rats were injected with ML385 (an Nrf2-inhibitor) 30 minutes before HIBI. Ferroptosis was evaluated by measuring glutathione peroxidase 4 (GPx4), solute carrier family 7 member 11 (SLC7A11, also known as xCT), glutathione (GSH), cysteine, iron, malondialdehyde (MDA) levels, and mitochondrial morphology. Nrf2 and heme oxygenase-1 (HO-1) expression were determined to explore the signaling pathways involved in SPC-mediated neuroprotection. Brain morphology, left/right hemisphere weight ratios, and Nissl staining were measured to assess brain damage. The Morris water maze was conducted to assess long-term learning and memory abilities.
SPC alleviated HIBI-induced cysteine depletion-induced (HIBI versus SPC, xCT/β-tubulin ratio: -0.435 [95% CI, -0.727 to -0.143], P = .003; Cysteine (% of Sham): -29.8 [95% CI, -39.4 to -20.2], P < .001; GSH (% of Sham): -46.5 [95% CI, -54.6 to -38.4], P < .001) and GPx4 inhibition-induced ferroptosis (HIBI versus SPC, GPx4/β-tubulin ratio: -0.287 [95% CI, -0.514 to -0.0603], P = .01). Compared with the HIBI group, the SPC group showed improved learning and memory abilities (HIBI versus SPC, platform crossings: -4 times [95% CI, -7 to -1], P = .002; escape latency: 46 seconds [95% CI, 24 to 68], P < .001), reduced brain damage (HIBI versus SPC, weight ratio of left/right cerebral hemispheres: -13.1 [95% CI, -15.7 to -10.4], P < .001; neuronal density ratio: -0.450 [-0.620 to -0.280], P < .001), and increased Nrf2 and HO-1 protein levels (HIBI versus SPC, Nrf2/β-tubulin ratio: -1.89 [95% CI, -2.82 to -0.970], P < .001; HO-1/β-tubulin ratio: -1.08 [95% CI, -1.73 to -0.442], P < .001). Inhibiting Nrf2 via ML385 partly reversed SPC-mediated neuroprotection (SPC versus SPC+ML385, weight ratio of left/right cerebral hemispheres: 12.4 [95% CI, 9.73-15.1], P < .001; neuronal density ratio: 0.412 [95% CI, 0.242-0.582], P < .001), accompanied by decreased HO-1 expression (SPC versus SPC+ML385, HO-1/β-tubulin ratio: 1.70 [95% CI, 1.05-2.34], P < .001).
SPC inhibits both cysteine depletion- and GPx4 inhibition-induced ferroptosis by regulating Nrf2/HO-1 signaling to protect against HIBI.
七氟醚保护大脑免受缺氧缺血性脑损伤（HIBI）的机制尚不清楚。铁死亡发生在HIBI过程中，并受核因子红细胞2相关因子2（Nrf2）调控。本研究探讨Nrf2调控的铁死亡在七氟醚后处理（SPC）介导的HIBI神经保护中的作用。
在7日龄大鼠中诱导HIBI。HIBI后立即进行SPC（2.5%，30分钟），部分大鼠在HIBI前30分钟注射ML385（一种Nrf2抑制剂）。通过测量谷胱甘肽过氧化物酶4（GPx4）、溶质载体家族7成员11（SLC7A11，也称为xCT）、谷胱甘肽（GSH）、半胱氨酸、铁、丙二醛（MDA）水平及线粒体形态来评估铁死亡。检测Nrf2和血红素加氧酶-1（HO-1）表达，以探索SPC介导的神经保护所涉及的信号通路。测量脑形态、左右半球重量比及尼氏染色以评估脑损伤。进行莫里斯水迷宫实验以评估长期学习和记忆能力。
SPC减轻了HIBI诱导的半胱氨酸耗竭诱导的（HIBI组与SPC组比较，xCT/β-微管蛋白比值：-0.435[95%CI，-0.727至-0.143]，P = 0.003；半胱氨酸（假手术组的百分比）：-29.8[95%CI，-39.4至-20.2]，P < 0.001；GSH（假手术组的百分比）：-46.5[95%CI，-54.6至-38.4]，P < 0.001）和GPx4抑制诱导的铁死亡（HIBI组与SPC组比较，GPx4/β-微管蛋白比值：-0.287[95%CI，-0.514至-0.0603]，P = 0.01）。与HIBI组相比，SPC组的学习和记忆能力得到改善（HIBI组与SPC组比较，平台穿越次数：-4次[95%CI，-7至-1]，P = 0.002；逃避潜伏期：46秒[95%CI，24至68]，P < 0.001），脑损伤减轻（HIBI组与SPC组比较，左右脑半球重量比：-13.1[95%CI，-15.7至-10.4]，P < 0.001；神经元密度比：-0.450[-0.620至-0.280]，P < 0.001），Nrf2和HO-1蛋白水平升高（HIBI组与SPC组比较，Nrf2/β-微管蛋白比值：-1.89[95%CI，-2.82至-0.970]，P < 0.001；HO-1/β-微管蛋白比值：-1.08[95%CI，-1.73至-0.442]，P < 0.001）。通过ML385抑制Nrf2部分逆转了SPC介导的神经保护作用（SPC组与SPC + ML385组比较，左右脑半球重量比：12.4[95%CI，9.73 - 15.1]，P < 0.001；神经元密度比：0.412[95%CI，0.242 - 0.582]，P < 0.001），同时HO-1表达降低（SPC组与SPC + ML385组比较, HO-1/β-微管蛋白比值：1.70[95%CI，1.05 - 2.34]，P < 0.001）。
SPC通过调节Nrf2/HO-1信号通路抑制半胱氨酸耗竭和GPx4抑制诱导的铁死亡，从而预防HIBI。
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