Influence of Sevoflurane Postconditioning on Hypoxic-Ischemic Brain Injury via Nrf2-Regulated Ferroptosis in Neonatal Rats.

Anesthesia & Analgesia Pub Date : 2025-05-16 DOI:10.1213/ane.0000000000007547

Chang Li,Ziyi Wu,Hang Xue,Qiushi Gao,Shihui Kuai,Ping Zhao

{"title":"Influence of Sevoflurane Postconditioning on Hypoxic-Ischemic Brain Injury via Nrf2-Regulated Ferroptosis in Neonatal Rats.","authors":"Chang Li,Ziyi Wu,Hang Xue,Qiushi Gao,Shihui Kuai,Ping Zhao","doi":"10.1213/ane.0000000000007547","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nThe 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.\r\n\r\nMETHODS\r\nHIBI 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.\r\n\r\nRESULTS\r\nSPC 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).\r\n\r\nCONCLUSIONS\r\nSPC inhibits both cysteine depletion- and GPx4 inhibition-induced ferroptosis by regulating Nrf2/HO-1 signaling to protect against HIBI.","PeriodicalId":7799,"journal":{"name":"Anesthesia & Analgesia","volume":"6 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anesthesia & Analgesia","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1213/ane.0000000000007547","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}

引用次数: 0

Abstract

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS SPC inhibits both cysteine depletion- and GPx4 inhibition-induced ferroptosis by regulating Nrf2/HO-1 signaling to protect against HIBI.

查看原文本刊更多论文

七氟醚后处理通过nrf2调控的铁下沉对新生大鼠缺氧缺血性脑损伤的影响。

背景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。HIBI期间发生铁下垂，并受核因子红细胞2相关因子2 （Nrf2）的调节。本研究探讨了nrf2调控的铁下沉在HIBI期间七氟烷后处理（SPC）介导的神经保护中的作用。方法7日龄大鼠诱导shibi。HIBI后立即进行SPC（2.5%， 30分钟），部分大鼠在HIBI前30分钟注射nrf2抑制剂ML385。通过测定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）水平和线粒体形态来评估铁中毒。通过检测Nrf2和血红素加氧酶-1 （HO-1）的表达，探讨spc介导的神经保护的信号通路。测量脑形态学、左/右半球重量比和尼氏染色来评估脑损伤。Morris水迷宫测试小鼠的长期学习和记忆能力。结果SPC可减轻HIBI诱导的半胱氨酸消耗(HIBI vs SPC， xCT/β-微管蛋白比值：-0.435 [95% CI, -0.727 ~ -0.143], P = 0.003；半胱氨酸（占Sham的百分比）：-29.8 [95% CI, -39.4 ~ -20.2], P < 0.001；GSH（占Sham的百分比）：-46.5 [95% CI, -54.6至-38.4],P < .001)和GPx4抑制诱导的铁凋亡（HIBI与SPC相比，GPx4/β-微管蛋白比值：-0.287 [95% CI, -0.514至-0.0603],P = .01）。与HIBI组相比，SPC组表现出更好的学习和记忆能力(HIBI组与SPC组，平台交叉：-4倍[95% CI， -7至-1]，P = 0.002；逃避潜伏期：46秒[95% CI， 24 ~ 68], P < .001)，减少脑损伤(HIBI与SPC，左右脑半球重量比：-13.1 [95% CI, -15.7 ~ -10.4], P < .001；神经元密度比：-0.450 [-0.620 ~ -0.280],P < 0.001)， Nrf2和HO-1蛋白水平升高(HIBI与SPC相比，Nrf2/β-微管蛋白比：-1.89 [95% CI, -2.82 ~ -0.970], P < 0.001；HO-1 /β微管蛋白比例:-1.08(95%可信区间,-1.73至-0.442),P <措施)。通过ML385抑制Nrf2部分逆转SPC介导的神经保护(SPC vs SPC+ML385，左右脑半球重量比：12.4 [95% CI, 9.73-15.1], P < .001；神经元密度比：0.412 [95% CI, 0.242 ~ 0.582], P < .001)，并伴有HO-1表达降低（SPC与SPC+ML385相比，HO-1/β-微管蛋白比：1.70 [95% CI, 1.05 ~ 2.34], P < .001）。结论sspc通过调控Nrf2/HO-1信号通路抑制半胱氨酸缺失和GPx4抑制诱导的铁凋亡，从而对HIBI具有保护作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Anesthesia & Analgesia

自引率

0.00%

发文量