Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2022 Jul 29

PMID 35903552

Authors

Yilin Pang

Xinjie Liu

Xu Wang

Xuelian Shi

Lei Ma

Yan Zhang

Tiangang Zhou

Chenxi Zhao

Xu Zhang

Baoyou Fan

Jian Hao

Wenxiang Li

Xiaoqing Zhao

Rong Zhang

Songlin Zhou

Xiaohong Kong

Shiqing Feng

Xue Yao

Affiliations

Soon will be listed here.

Abstract

The FDA-approved drug edaravone has a neuroprotective effect on spinal cord injury (SCI) and many other central nervous system diseases. However, its molecular mechanism remains unclear. Since edaravone is a lipid peroxidation scavenger, we hypothesize that edaravone exerts its neuroprotective effect by inhibiting ferroptosis in SCI. Edaravone treatment after SCI upregulates glutathione peroxidase 4 (GPX4) and system Xc-light chain (xCT), which are anti-ferroptosis proteins. It downregulates pro-ferroptosis proteins Acyl-CoA synthetase long-chain family member 4 (ACSL4) and 5-lipoxygenase (5-LOX). The most significant changes in edaravone treatment occur in the acute phase, two days post injury. Edaravone modulates neuronal GPX4/ACSL4/5-LOX in the spinal segment below the lesion, which is critical for maintaining locomotion. Moreover, the GPX4/ACSL4/5-LOX in motor neuron is also modulated by edaravone in the spinal cord. Therefore, secondary injury below the lesion site is reversed by edaravone ferroptosis inhibition. The cytokine array revealed that edaravone upregulated some anti-inflammatory cytokines such as IL-10, IL-13, and adiponectin. Edaravone reduced microgliosis and astrogliosis, indicating reduced neuroinflammation. Edaravone has a long-term effect on neuronal survival, spinal cord tissue sparing, and motor function recovery. In summary, we revealed a novel mechanism of edaravone in inhibiting neuronal ferroptosis in SCI. This mechanism may be generalizable to other neurological diseases.

Citing Articles

Ferroptosis and Its Potential Role in the Physiopathology of Skeletal Muscle Atrophy.

Sun C, Xiao J, Sun C, Tang C Int J Mol Sci. 2024; 25(22).

PMID: 39596528 PMC: 11595065. DOI: 10.3390/ijms252212463.

Edaravone mitigates calcium oxalate-induced renal tubular epithelial cell injury by inhibiting autophagy-mediated ferroptosis.

Chen W, Cao Z, Wang S Naunyn Schmiedebergs Arch Pharmacol. 2024; .

PMID: 39576301 DOI: 10.1007/s00210-024-03630-6.

The role of ACSL4 in stroke: mechanisms and potential therapeutic target.

Zhuo B, Qin C, Deng S, Jiang H, Si S, Tao F Mol Cell Biochem. 2024; .

PMID: 39496916 DOI: 10.1007/s11010-024-05150-6.

Efficacy and safety of edaravone combined with Ginkgo Leaf Extract and Dipyridamole in the treatment of acute cerebral infarction: A systematic review and meta-analysis.

Lyu Y, Xu B Medicine (Baltimore). 2024; 103(44):e40223.

PMID: 39496028 PMC: 11537593. DOI: 10.1097/MD.0000000000040223.

Circulatory Indicators of Lipid Peroxidation, the Driver of Ferroptosis, Reflect Differences between Relapsing-Remitting and Progressive Multiple Sclerosis.

Stojkovic L, Djordjevic A, Stefanovic M, Stankovic A, Dincic E, Djuric T Int J Mol Sci. 2024; 25(20).

PMID: 39456806 PMC: 11507982. DOI: 10.3390/ijms252011024.

References

Zhang Y, Sun C, Zhao C, Hao J, Zhang Y, Fan B . Ferroptosis inhibitor SRS 16-86 attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury. Brain Res. 2018; 1706:48-57. DOI: 10.1016/j.brainres.2018.10.023. View

Proneth B, Conrad M . Ferroptosis and necroinflammation, a yet poorly explored link. Cell Death Differ. 2018; 26(1):14-24. PMC: 6294786. DOI: 10.1038/s41418-018-0173-9. View

Fan B, Pang Y, Li W, Zhao C, Zhang Y, Wang X . Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res. 2020; 16(3):561-566. PMC: 7996026. DOI: 10.4103/1673-5374.293157. View

Yao X, Zhang Y, Hao J, Duan H, Zhao C, Sun C . Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis. Neural Regen Res. 2018; 14(3):532-541. PMC: 6334606. DOI: 10.4103/1673-5374.245480. View

Verma N, Vinik Y, Saroha A, Nair N, Ruppin E, Mills G . Synthetic lethal combination targeting BET uncovered intrinsic susceptibility of TNBC to ferroptosis. Sci Adv. 2020; 6(34). PMC: 7442484. DOI: 10.1126/sciadv.aba8968. View

Jiao S, Yao X, Liu Y, Wang Q, Zeng F, Lu J . Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc Natl Acad Sci U S A. 2015; 112(16):5225-30. PMC: 4413288. DOI: 10.1073/pnas.1422998112. View

Masuda T, Shimazawa M, Hara H . Retinal Diseases Associated with Oxidative Stress and the Effects of a Free Radical Scavenger (Edaravone). Oxid Med Cell Longev. 2017; 2017:9208489. PMC: 5286467. DOI: 10.1155/2017/9208489. View

Yamamoto Y, Kuwahara T, Watanabe K . Antioxidant activity of 3-methyl-1-phenyl-2-pyrazolin-5-one. Redox Rep. 2016; 2(5):333-8. DOI: 10.1080/13510002.1996.11747069. View

Courtine G, Sofroniew M . Spinal cord repair: advances in biology and technology. Nat Med. 2019; 25(6):898-908. DOI: 10.1038/s41591-019-0475-6. View

10.

Bracken M, Shepard M, Holford T, Leo-Summers L, Aldrich E, Fazl M . Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord.... JAMA. 1997; 277(20):1597-604. View

11.

Reznik S, Tiwari A, Ashby Jr C . Edaravone: A potential treatment for the COVID-19-induced inflammatory syndrome?. Pharmacol Res. 2020; 160:105055. PMC: 7326414. DOI: 10.1016/j.phrs.2020.105055. View

12.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

13.

Hu X, Xu Y, Xu H, Jin C, Zhang H, Su H . Progress in Understanding Ferroptosis and Its Targeting for Therapeutic Benefits in Traumatic Brain and Spinal Cord Injuries. Front Cell Dev Biol. 2021; 9:705786. PMC: 8371332. DOI: 10.3389/fcell.2021.705786. View

14.

Huang H, Young W, Skaper S, Chen L, Moviglia G, Saberi H . Clinical Neurorestorative Therapeutic Guidelines for Spinal Cord Injury (IANR/CANR version 2019). J Orthop Translat. 2020; 20:14-24. PMC: 6939117. DOI: 10.1016/j.jot.2019.10.006. View

15.

Ishii H, Petrenko A, Sasaki M, Satoh Y, Kamiya Y, Tobita T . Free radical scavenger edaravone produces robust neuroprotection in a rat model of spinal cord injury. Brain Res. 2018; 1682:24-35. DOI: 10.1016/j.brainres.2017.12.035. View

16.

Shin D, Kim E, Lee J, Roh J . Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018; 129:454-462. DOI: 10.1016/j.freeradbiomed.2018.10.426. View

17.

Venniro M, Zhang M, Caprioli D, Hoots J, Golden S, Heins C . Volitional social interaction prevents drug addiction in rat models. Nat Neurosci. 2018; 21(11):1520-1529. PMC: 7386559. DOI: 10.1038/s41593-018-0246-6. View

18.

Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K . Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell. 2018; 172(3):409-422.e21. DOI: 10.1016/j.cell.2017.11.048. View

19.

Yao X, Sun C, Fan B, Zhao C, Zhang Y, Duan H . Neurotropin exerts neuroprotective effects after spinal cord injury by inhibiting apoptosis and modulating cytokines. J Orthop Translat. 2021; 26:74-83. PMC: 7773959. DOI: 10.1016/j.jot.2020.02.011. View

20.

Genovese T, Rossi A, Mazzon E, Di Paola R, Muia C, Caminiti R . Effects of zileuton and montelukast in mouse experimental spinal cord injury. Br J Pharmacol. 2007; 153(3):568-82. PMC: 2241786. DOI: 10.1038/sj.bjp.0707577. View