Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Fari Ryan, Christian Blex, The Dung Ngo, Marcel A. Kopp, Bernhard Michalke, Vivek Venkataramani, Laura Curran, Jan M. Schwab, Klemens Ruprecht, Carolin Otto, Priya Jhelum, Antje Kroner, Samuel David
{"title":"Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury","authors":"Fari Ryan,&nbsp;Christian Blex,&nbsp;The Dung Ngo,&nbsp;Marcel A. Kopp,&nbsp;Bernhard Michalke,&nbsp;Vivek Venkataramani,&nbsp;Laura Curran,&nbsp;Jan M. Schwab,&nbsp;Klemens Ruprecht,&nbsp;Carolin Otto,&nbsp;Priya Jhelum,&nbsp;Antje Kroner,&nbsp;Samuel David","doi":"10.1007/s00401-024-02758-2","DOIUrl":null,"url":null,"abstract":"<div><p>We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe<sup>2+</sup>) to ferric iron (Fe<sup>3+</sup>) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"147 1","pages":""},"PeriodicalIF":9.3000,"publicationDate":"2024-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02758-2.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s00401-024-02758-2","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

We show that redox active iron can induce a regulated form of non-apoptotic cell death and tissue damage called ferroptosis that can contribute to secondary damage and functional loss in the acute and chronic periods after spinal cord injury (SCI) in young, adult, female mice. Phagocytosis of red blood cells at sites of hemorrhage is the main source of iron derived from hemoglobin after SCI. Expression of hemeoxygenase-1 that induces release of iron from heme, is increased in spinal cord macrophages 7 days after injury. While iron is stored safely in ferritin in the injured spinal cord, it can, however, be released by NCOA4-mediated shuttling of ferritin to autophagosomes for degradation (ferritinophagy). This leads to the release of redox active iron that can cause free radical damage. Expression of NCOA4 is increased after SCI, mainly in macrophages. Increase in the ratio of redox active ferrous (Fe2+) to ferric iron (Fe3+) is also detected after SCI by capillary electrophoresis inductively coupled mass spectrometry. These changes are accompanied by other hallmarks of ferroptosis, i.e., deficiency in various elements of the antioxidant glutathione (GSH) pathway. We also detect increases in enzymes that repair membrane lipids (ACSL4 and LPCAT3) and thus promote on-going ferroptosis. These changes are associated with increased levels of 4-hydroxynonenal (4-HNE), a toxic lipid peroxidation product. Mice with mild SCI (30 kdyne force) treated with the ferroptosis inhibitor (UAMC-3203-HCL) either early or delayed times after injury showed improvement in locomotor recovery and secondary damage. Cerebrospinal fluid and serum samples from human SCI cases show evidence of increased iron storage (ferritin), and other iron related molecules, and reduction in GSH. Collectively, these data suggest that ferroptosis contributes to secondary damage after SCI and highlights the possible use of ferroptosis inhibitors to treat SCI.

Abstract Image

铁蛋白沉积抑制剂可改善轻度脊髓损伤早期和延迟治疗后的疗效
我们的研究表明,氧化还原活性铁能诱导一种称为铁凋亡的非凋亡性细胞死亡和组织损伤的调节形式,这种损伤可导致年轻成年雌性小鼠脊髓损伤(SCI)后急性期和慢性期的继发性损伤和功能丧失。出血部位红细胞的吞噬作用是脊髓损伤后血红蛋白中铁的主要来源。损伤 7 天后,脊髓巨噬细胞中可诱导从血红素中释放铁的血红素氧化酶-1 的表达增加。虽然铁在损伤脊髓中安全地储存在铁蛋白中,但它可以通过 NCOA4 介导的铁蛋白穿梭到自噬体中降解(噬铁蛋白)而释放出来。这将导致氧化还原活性铁的释放,从而造成自由基损伤。SCI 后,NCOA4 的表达增加,主要是在巨噬细胞中。通过毛细管电泳电感耦合质谱法,还可检测到 SCI 后氧化还原活性亚铁(Fe2+)与铁(Fe3+)的比率增加。伴随这些变化的还有铁中毒的其他特征,即抗氧化谷胱甘肽(GSH)途径中各种元素的缺乏。我们还检测到膜脂质修复酶(ACSL4 和 LPCAT3)的增加,从而促进了持续的铁变态反应。这些变化与有毒的脂质过氧化产物--4-羟基壬烯醛(4-HNE)含量的增加有关。轻度 SCI(30 kdyne 力)小鼠在受伤后早期或延迟使用铁蛋白沉积抑制剂(UAMC-3203-HCL)治疗后,运动恢复和继发性损伤均有所改善。人体 SCI 病例的脑脊液和血清样本显示铁储存(铁蛋白)和其他铁相关分子增加,以及 GSH 减少。总之,这些数据表明,铁蛋白沉积是造成 SCI 后继发性损伤的原因之一,并强调了使用铁蛋白沉积抑制剂治疗 SCI 的可能性。
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
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信