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多次七氟醚暴露于妊娠中期会诱发由 15LO2 介导的铁死亡引发的发育中大脑的神经毒性。

Multiple sevoflurane exposures during mid-trimester induce neurotoxicity in the developing brain initiated by 15LO2-Mediated ferroptosis.

机构信息

Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, China.

出版信息

CNS Neurosci Ther. 2023 Oct;29(10):2972-2985. doi: 10.1111/cns.14236. Epub 2023 Jun 7.

DOI:10.1111/cns.14236
PMID:37287422
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10493671/
Abstract

AIMS

Mid-gestational sevoflurane exposure may induce notable long-term neurocognitive impairment in offspring. This study was designed to investigate the role and potential mechanism of ferroptosis in developmental neurotoxicity induced by sevoflurane in the second trimester.

METHODS

Pregnant rats on day 13 of gestation (G13) were treated with or without 3.0% sevoflurane, Ferrostatin-1 (Fer-1), PD146176, or Ku55933 on three consecutive days. Mitochondrial morphology, ferroptosis-relative proteins, malondialdehyde (MDA) levels, total iron content, and glutathione peroxidase 4 (GPX4) activities were measured. Hippocampal neuronal development in offspring was also examined. Subsequently, 15-lipoxygenase 2 (15LO2)-phosphatidylethanolamine binding protein 1 (PEBP1) interaction and expression of Ataxia telangiectasia mutated (ATM) and its downstream proteins were also detected. Furthermore, Morris water maze (MWM) and Nissl's staining were applied to estimate the long-term neurotoxic effects of sevoflurane.

RESULTS

Ferroptosis mitochondria were observed after maternal sevoflurane exposures. Sevoflurane elevated MDA and iron levels while inhibiting GPX4 activity, and resultant long-term learning and memory dysfunction, which were alleviated by Fer-1, PD146176, and Ku55933. Sevoflurane could enhance 15LO2-PEBP1 interaction and activate ATM and its downstream P53/SAT1 pathway, which might be attributed to excessive p-ATM nuclear translocation.

CONCLUSION

This study proposes that 15LO2-mediated ferroptosis might contribute to neurotoxicity induced by maternal sevoflurane anesthesia during the mid-trimester in the offspring and its mechanism may be ascribed to hyperactivation of ATM and enhancement of 15LO2-PEBP1 interaction, indicating a potential therapeutic target for ameliorating sevoflurane-induced neurotoxicity.

摘要

目的

中孕期七氟醚暴露可能导致后代明显的长期神经认知障碍。本研究旨在探讨铁死亡在二氢嘧啶脱氢酶抑制剂诱导的发育期神经毒性中的作用及潜在机制。

方法

妊娠第 13 天（G13）的孕鼠连续 3 天用或不用 3.0%七氟醚、铁抑素-1（Fer-1）、PD146176 或 Ku55933 处理。测量线粒体形态、铁死亡相关蛋白、丙二醛（MDA）水平、总铁含量和谷胱甘肽过氧化物酶 4（GPX4）活性。还检查了子代海马神经元发育情况。随后，还检测了 15-脂氧合酶 2（15LO2）-磷酸乙醇胺结合蛋白 1（PEBP1）相互作用以及共济失调毛细血管扩张突变基因（ATM）及其下游蛋白的表达。此外，还应用 Morris 水迷宫（MWM）和尼氏染色来评估七氟醚的长期神经毒性作用。

结果

母体七氟醚暴露后观察到铁死亡线粒体。七氟醚升高 MDA 和铁水平，同时抑制 GPX4 活性，导致长期学习和记忆功能障碍，Fer-1、PD146176 和 Ku55933 可减轻这些障碍。七氟醚可以增强 15LO2-PEBP1 相互作用并激活 ATM 及其下游 P53/SAT1 途径，这可能归因于过度的 p-ATM 核转位。

结论

本研究提出，15LO2 介导的铁死亡可能导致母体七氟醚麻醉中孕期对子代的神经毒性，其机制可能归因于 ATM 的过度激活和增强 15LO2-PEBP1 相互作用，表明改善七氟醚诱导的神经毒性的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/bfd910fd7863/CNS-29-2972-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/7048403788ef/CNS-29-2972-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/a41cfd4751c6/CNS-29-2972-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/5468b2796cac/CNS-29-2972-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/3e84f174e618/CNS-29-2972-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/b328514508e6/CNS-29-2972-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/bfd910fd7863/CNS-29-2972-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/7048403788ef/CNS-29-2972-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/a41cfd4751c6/CNS-29-2972-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/5468b2796cac/CNS-29-2972-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/3e84f174e618/CNS-29-2972-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/b328514508e6/CNS-29-2972-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e93d/10493671/bfd910fd7863/CNS-29-2972-g002.jpg

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