Ferroptosis Inhibition Protects Vascular Endothelial Cells and Maintains Integrity of the Blood-spinal Cord Barrier After Spinal Cord Injury

Overview

Journal Neural Regen Res

Date 2023 Jun 7

PMID 37282479

Authors

Wenxiang Li

Xiaoqing Zhao

Rong Zhang

Xinjie Liu

Zhangyang Qi

Yang Zhang

Weiqi Yang

Yilin Pang

Chenxi Zhao

Baoyou Fan

Ning Ran

Jiawei Zhang

Xiaohong Kong

Shiqing Feng

Xue Yao

Affiliations

Soon will be listed here.

Abstract

Maintaining the integrity of the blood-spinal cord barrier is critical for the recovery of spinal cord injury. Ferroptosis contributes to the pathogenesis of spinal cord injury. We hypothesized that ferroptosis is involved in disruption of the blood-spinal cord barrier. In this study, we administered the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal cord injury in rats. Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord injury. Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein. Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury, as shown by the immunofluorescence of an endothelial cell marker (rat endothelium cell antigen-1, RECA-1) and ferroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Liproxstatin-1 reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase. Furthermore, inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment. In summary, liproxstatin-1 improved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-spinal cord barrier integrity.

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References

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

Betterton R, Abdullahi W, Williams E, Lochhead J, Brzica H, Stanton J . Regulation of Blood-Brain Barrier Transporters by Transforming Growth Factor-/Activin Receptor-Like Kinase 1 Signaling: Relevance to the Brain Disposition of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (i.e., Statins). Drug Metab Dispos. 2022; 50(7):942-956. PMC: 11022862. DOI: 10.1124/dmd.121.000781. View

Beck K, Nguyen H, Galvan M, Salazar D, Woodruff T, Anderson A . Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain. 2010; 133(Pt 2):433-47. PMC: 2858013. DOI: 10.1093/brain/awp322. 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

Chen Y, Liu S, Li J, Li Z, Quan J, Liu X . The Latest View on the Mechanism of Ferroptosis and Its Research Progress in Spinal Cord Injury. Oxid Med Cell Longev. 2020; 2020:6375938. PMC: 7474794. DOI: 10.1155/2020/6375938. View

Chen B, Wang H, Lv C, Mao C, Cui Y . Long non-coding RNA H19 protects against intracerebral hemorrhage injuries via regulating microRNA-106b-5p/acyl-CoA synthetase long chain family member 4 axis. Bioengineered. 2021; 12(1):4004-4015. PMC: 8806815. DOI: 10.1080/21655979.2021.1951070. View

Gao S, Zhou L, Lu J, Fang Y, Wu H, Xu W . Cepharanthine Attenuates Early Brain Injury after Subarachnoid Hemorrhage in Mice via Inhibiting 15-Lipoxygenase-1-Mediated Microglia and Endothelial Cell Ferroptosis. Oxid Med Cell Longev. 2022; 2022:4295208. PMC: 8850040. DOI: 10.1155/2022/4295208. View

Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey M, Baker M . The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol. 2020; 18(7):e3000410. PMC: 7360023. DOI: 10.1371/journal.pbio.3000410. View

Sharma H . Early microvascular reactions and blood-spinal cord barrier disruption are instrumental in pathophysiology of spinal cord injury and repair: novel therapeutic strategies including nanowired drug delivery to enhance neuroprotection. J Neural Transm (Vienna). 2010; 118(1):155-76. DOI: 10.1007/s00702-010-0514-4. View

10.

Jin L, Li J, Wang K, Xia W, Zhu Z, Wang C . Blood-Spinal Cord Barrier in Spinal Cord Injury: A Review. J Neurotrauma. 2020; 38(9):1203-1224. DOI: 10.1089/neu.2020.7413. View

11.

Li F, Wang H, Chen H, Guo J, Dang X, Ru Y . Mechanism of Ferroptosis and Its Role in Spinal Cord Injury. Front Neurol. 2022; 13:926780. PMC: 9218271. DOI: 10.3389/fneur.2022.926780. View

12.

Haque A, Capone M, Matzelle D, Cox A, Banik N . Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats. Neurochem Res. 2017; 42(10):2777-2787. PMC: 5685929. DOI: 10.1007/s11064-017-2291-z. View

13.

Pang Y, Liu X, Wang X, Shi X, Ma L, Zhang Y . Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury. Front Cell Dev Biol. 2022; 10:849854. PMC: 9318422. DOI: 10.3389/fcell.2022.849854. View

14.

Lee S, Rosen S, Weinstein P, van Rooijen N, Noble-Haeusslein L . Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma. 2011; 28(9):1893-907. PMC: 3172879. DOI: 10.1089/neu.2011.1860. View

15.

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

16.

Fan B, Wei Z, Yao X, Shi G, Cheng X, Zhou X . Microenvironment Imbalance of Spinal Cord Injury. Cell Transplant. 2018; 27(6):853-866. PMC: 6050904. DOI: 10.1177/0963689718755778. View

17.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

18.

Drummen G, van Liebergen L, Op den Kamp J, Post J . C11-BODIPY(581/591), an oxidation-sensitive fluorescent lipid peroxidation probe: (micro)spectroscopic characterization and validation of methodology. Free Radic Biol Med. 2002; 33(4):473-90. DOI: 10.1016/s0891-5849(02)00848-1. View

19.

Chen X, Zhang B, Liu T, Feng M, Zhang Y, Zhang C . Liproxstatin-1 Attenuates Morphine Tolerance through Inhibiting Spinal Ferroptosis-like Cell Death. ACS Chem Neurosci. 2019; 10(12):4824-4833. DOI: 10.1021/acschemneuro.9b00539. View

20.

Neirinckx V, Coste C, Franzen R, Gothot A, Rogister B, Wislet S . Neutrophil contribution to spinal cord injury and repair. J Neuroinflammation. 2014; 11:150. PMC: 4174328. DOI: 10.1186/s12974-014-0150-2. View