Skip to main content

Advertisement

SpringerLink
Log in

Ferrostatin-1 Alleviates White Matter Injury Via Decreasing Ferroptosis Following Spinal Cord Injury

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Spinal cord injury (SCI), a devastating neurological impairment, usually imposes a long-term psychological stress and high socioeconomic burden for the sufferers and their family. Recent researchers have paid arousing attention to white matter injury and the underlying mechanism following SCI. Ferroptosis has been revealed to be associated with diverse diseases including stroke, cancer, and kidney degeneration. Ferrostatin-1, a potent inhibitor of ferroptosis, has been illustrated to curb ferroptosis in neurons, subsequently improving functional recovery after traumatic brain injury (TBI) and SCI. However, the role of ferroptosis in white matter injury and the therapeutic effect of ferrostatin-1 on SCI are still unknown. Here, our results indicated that ferroptosis played a pivotal role in the secondary white matter injury, and ferrostatin-1 could reduce iron and reactive oxygen species (ROS) accumulation and downregulate the ferroptosis-related genes and its products of IREB2 and PTGS2 to further inhibit ferroptosis in oligodendrocyte, finally reducing white matter injury and promoting functional recovery following SCI in rats. Meanwhile, the results demonstrated that ferrostatin-1 held the potential of inhibiting the activation of reactive astrocyte and microglia. Mechanically, the present study deciphers the potential mechanism of white matter damage, which enlarges the therapeutic effects of ferrostatin-1 on SCI and even in other central nervous system (CNS) diseases existing ferroptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

SCI:

Spinal cord injury

TBI:

Traumatic brain injury

ROS:

Reactive oxygen species

CNS:

Central nervous system

ASIC 1a:

Acid-sensing ion channel 1a

GPER1:

G-protein coupled estrogen receptor 1

NSCs:

Neural stem cells

DFX:

Deferoxamine

DMT1:

Divalent metal transporter 1

RCD:

Regulated cell death

BBB:

Blood–brain barrier

OPCs:

Oligodendrocyte progenitor cells

DMEM:

Dulbecco’s modified Eagle’s medium

PDGF:

Platelet-derived growth factor

PBS:

Phosphate-buffered saline

IHC:

Immunohistochemistry

DAB:

3-Diaminobenzidine

BCA:

Bicinchoninic acid

HRP:

Horseradish peroxidase

RT-qPCR:

Reverse transcription-quantitative polymerase chain reaction

TEM:

Transmission electron microscopy

References

  1. Hutson TH, Di Giovanni S (2019) The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration. Nat Rev Neurol 15(12):732–745. https://doi.org/10.1038/s41582-019-0280-3

    Article  PubMed  Google Scholar 

  2. Hu R, Sun H, Zhang Q, Chen J, Wu N, Meng H, Cui G, Hu S, Li F, Lin J, Wan Q, Feng H (2012) G-protein coupled estrogen receptor 1 mediated estrogenic neuroprotection against spinal cord injury. Crit Care Med 40(12):3230–3237. https://doi.org/10.1097/CCM.0b013e3182657560

    Article  CAS  PubMed  Google Scholar 

  3. Hu SL, Lu PG, Zhang LJ, Li F, Chen Z, Wu N, Meng H, Lin JK, Feng H (2012) In vivo magnetic resonance imaging tracking of SPIO-labeled human umbilical cord mesenchymal stem cells. J Cell Biochem 113(3):1005–1012. https://doi.org/10.1002/jcb.23432

    Article  CAS  PubMed  Google Scholar 

  4. Hu R, Duan B, Wang D, Yu Y, Li W, Luo H, Lu P, Lin J, Zhu G, Wan Q, Feng H (2011) Role of acid-sensing ion channel 1a in the secondary damage of traumatic spinal cord injury. Ann Surg 254(2):353–362. https://doi.org/10.1097/SLA.0b013e31822645b4

    Article  PubMed  Google Scholar 

  5. Chen J, Hu R, Ge H, Duanmu W, Li Y, Xue X, Hu S, Feng H (2015) G-protein-coupled receptor 30-mediated antiapoptotic effect of estrogen on spinal motor neurons following injury and its underlying mechanisms. Mol Med Rep 12(2):1733–1740. https://doi.org/10.3892/mmr.2015.3601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li L, Xiong ZY, Qian ZM, Zhao TZ, Feng H, Hu S, Hu R, Ke Y, Lin J (2014) Complement C5a is detrimental to histological and functional locomotor recovery after spinal cord injury in mice. Neurobiol Dis 66:74–82. https://doi.org/10.1016/j.nbd.2014.02.008

    Article  CAS  PubMed  Google Scholar 

  7. Yuan J, Liu W, Zhu H, Chen Y, Zhang X, Li L, Chu W, Wen Z, Feng H, Lin J (2017) Curcumin inhibits glial scar formation by suppressing astrocyte-induced inflammation and fibrosis in vitro and in vivo. Brain Res 1655:90–103. https://doi.org/10.1016/j.brainres.2016.11.002

    Article  CAS  PubMed  Google Scholar 

  8. Xia Y, Zhao T, Li J, Li L, Hu R, Hu S, Feng H, Lin J (2008) Antisense vimentin cDNA combined with chondroitinase ABC reduces glial scar and cystic cavity formation following spinal cord injury in rats. Biochem Biophys Res Commun 377(2):562–566. https://doi.org/10.1016/j.bbrc.2008.10.024

    Article  CAS  PubMed  Google Scholar 

  9. Xia Y, Yan Y, Xia H, Zhao T, Chu W, Hu S, Feng H, Lin J (2015) Antisense vimentin cDNA combined with chondroitinase ABC promotes axon regeneration and functional recovery following spinal cord injury in rats. Neurosci Lett 590:74–79. https://doi.org/10.1016/j.neulet.2015.01.073

    Article  CAS  PubMed  Google Scholar 

  10. Hu SL, Luo HS, Li JT, Xia YZ, Li L, Zhang LJ, Meng H, Cui GY, Chen Z, Wu N, Lin JK, Zhu G, Feng H (2010) Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. Crit Care Med 38(11):2181–2189. https://doi.org/10.1097/CCM.0b013e3181f17c0e

    Article  PubMed  Google Scholar 

  11. Chu W, Yuan J, Huang L, Xiang X, Zhu H, Chen F, Chen Y, Lin J, Feng H (2015) Valproic acid arrests proliferation but promotes neuronal differentiation of adult spinal NSPCs from SCI rats. Neurochem Res 40(7):1472–1486. https://doi.org/10.1007/s11064-015-1618-x

    Article  CAS  PubMed  Google Scholar 

  12. Chen F, Wang H, Xiang X, Yuan J, Chu W, Xue X, Zhu H, Ge H, Zou M, Feng H, Lin J (2014) Curcumin increased the differentiation rate of neurons in neural stem cells via wnt signaling in vitro study. J Surg Res 192(2):298–304. https://doi.org/10.1016/j.jss.2014.06.026

    Article  CAS  PubMed  Google Scholar 

  13. Mekhail M, Almazan G, Tabrizian M (2012) Oligodendrocyte-protection and remyelination post-spinal cord injuries: a review. Prog Neurobiol 96(3):322–339. https://doi.org/10.1016/j.pneurobio.2012.01.008

    Article  CAS  PubMed  Google Scholar 

  14. Fehlings MG, Tator CH (1995) The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury. Exp Neurol 132(2):220–228. https://doi.org/10.1016/0014-4886(95)90027-6

    Article  CAS  PubMed  Google Scholar 

  15. Kakulas BA (1999) A review of the neuropathology of human spinal cord injury with emphasis on special features. J Spinal Cord Med 22(2):119–124. https://doi.org/10.1080/10790268.1999.11719557

    Article  CAS  PubMed  Google Scholar 

  16. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81(2):871–927. https://doi.org/10.1152/physrev.2001.81.2.871

    Article  CAS  PubMed  Google Scholar 

  17. Juurlink BH, Thorburne SK, Hertz L (1998) Peroxide-scavenging deficit underlies oligodendrocyte susceptibility to oxidative stress. Glia 22(4):371–378. https://doi.org/10.1002/(sici)1098-1136(199804)22:4%3c371::aid-glia6%3e3.0.co;2-6

    Article  CAS  PubMed  Google Scholar 

  18. Thorburne SK, Juurlink BH (1996) Low glutathione and high iron govern the susceptibility of oligodendroglial precursors to oxidative stress. J Neurochem 67(3):1014–1022. https://doi.org/10.1046/j.1471-4159.1996.67031014.x

    Article  CAS  PubMed  Google Scholar 

  19. Fan BY, Pang YL, Li WX, Zhao CX, Zhang Y, Wang X, Ning GZ, Kong XH, Liu C, Yao X, Feng SQ (2021) Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res 16(3):561–566. https://doi.org/10.4103/1673-5374.293157

    Article  PubMed  Google Scholar 

  20. Shi J, Tang R, Zhou Y, Xian J, Zuo C, Wang L, Wang J, Feng H, Hu S (2020) Attenuation of white matter damage following deferoxamine treatment in rats after spinal cord injury. World Neurosurg 137:e9–e17. https://doi.org/10.1016/j.wneu.2019.08.246

    Article  PubMed  Google Scholar 

  21. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Feng Z, Min L, Chen H, Deng W, Tan M, Liu H, Hou J (2021) Iron overload in the motor cortex induces neuronal ferroptosis following spinal cord injury. Redox Biol 43:101984. https://doi.org/10.1016/j.redox.2021.101984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chu J, Liu CX, Song R, Li QL (2020) Ferrostatin-1 protects HT-22 cells from oxidative toxicity. Neural Regen Res 15(3):528–536. https://doi.org/10.4103/1673-5374.266060

    Article  PubMed  Google Scholar 

  24. Miotto G, Rossetto M, Di Paolo ML, Orian L, Venerando R, Roveri A, Vučković AM, Bosello Travain V, Zaccarin M, Zennaro L, Maiorino M, Toppo S, Ursini F, Cozza G (2020) Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol 28:101328. https://doi.org/10.1016/j.redox.2019.101328

    Article  CAS  PubMed  Google Scholar 

  25. Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR (2018) Targeting Nrf2 to suppress ferroptosis and mitochondrial dysfunction in neurodegeneration. Front Neurosci 12:466. https://doi.org/10.3389/fnins.2018.00466

    Article  PubMed  PubMed Central  Google Scholar 

  26. Li S, Zhou C, Zhu Y, Chao Z, Sheng Z, Zhang Y, Zhao Y (2020) Ferrostatin-1 alleviates angiotensin II (Ang II)- induced inflammation and ferroptosis in astrocytes. Int Immunopharmacol 90:107179. https://doi.org/10.1016/j.intimp.2020.107179

    Article  CAS  PubMed  Google Scholar 

  27. Lu J, Xu F, Lu H (2020) LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53. Life Sci 260:118305. https://doi.org/10.1016/j.lfs.2020.118305

    Article  CAS  PubMed  Google Scholar 

  28. Shen L, Lin D, Li X, Wu H, Lenahan C, Pan Y, Xu W, Chen Y, Shao A, Zhang J (2020) Ferroptosis in acute central nervous system injuries: the future direction? Front Cell Dev Biol 8:594. https://doi.org/10.3389/fcell.2020.00594

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen B, Chen Z, Liu M, Gao X, Cheng Y, Wei Y, Wu Z, Cui D, Shang H (2019) Inhibition of neuronal ferroptosis in the acute phase of intracerebral hemorrhage shows long-term cerebroprotective effects. Brain Res Bull 153:122–132. https://doi.org/10.1016/j.brainresbull.2019.08.013

    Article  CAS  PubMed  Google Scholar 

  30. Li Y, Liu Y, Wu P, Tian Y, Liu B, Wang J, Bihl J, Shi H (2021) Inhibition of ferroptosis alleviates early brain injury after subarachnoid hemorrhage in vitro and in vivo via reduction of lipid peroxidation. Cell Mol Neurobiol 41(2):263–278. https://doi.org/10.1007/s10571-020-00850-1

    Article  CAS  PubMed  Google Scholar 

  31. Xie BS, Wang YQ, Lin Y, Mao Q, Feng JF, Gao GY, Jiang JY (2019) Inhibition of ferroptosis attenuates tissue damage and improves long-term outcomes after traumatic brain injury in mice. CNS Neurosci Ther 25(4):465–475. https://doi.org/10.1111/cns.13069

    Article  CAS  PubMed  Google Scholar 

  32. Chen X, Gao C, Yan Y, Cheng Z, Chen G, Rui T, Luo C, Gao Y, Wang T, Chen X, Tao L (2021) Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury. Exp Neurol 342:113762. https://doi.org/10.1016/j.expneurol.2021.113762

    Article  CAS  PubMed  Google Scholar 

  33. Qiu Y, Cao Y, Cao W, Jia Y, Lu N (2020) The application of ferroptosis in diseases. Pharmacol Res 159:104919. https://doi.org/10.1016/j.phrs.2020.104919

    Article  CAS  PubMed  Google Scholar 

  34. Yumnamcha T, Devi TS, Singh LP (2019) Auranofin mediates mitochondrial dysregulation and inflammatory cell death in human retinal pigment epithelial cells: implications of retinal neurodegenerative diseases. Front Neurosci 13:1065. https://doi.org/10.3389/fnins.2019.01065

    Article  PubMed  PubMed Central  Google Scholar 

  35. Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21. https://doi.org/10.1089/neu.1995.12.1

    Article  CAS  PubMed  Google Scholar 

  36. Basso DM, Beattie MS, Bresnahan JC (1996) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139(2):244–256. https://doi.org/10.1006/exnr.1996.0098

    Article  CAS  PubMed  Google Scholar 

  37. Serdar M, Mordelt A, Müser K, Kempe K, Felderhoff-Müser U, Herz J, Bendix I (2019) Detrimental impact of energy drink compounds on developing oligodendrocytes and neurons. Cells. https://doi.org/10.3390/cells8111381

    Article  PubMed  PubMed Central  Google Scholar 

  38. Han S, Tang Q, Chen R, Li Y, Shu J, Zhang X (2017) Hepatic iron overload is associated with hepatocyte apoptosis during Clonorchis sinensis infection. BMC Infect Dis 17(1):531. https://doi.org/10.1186/s12879-017-2630-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jiang X, Zhang J, Kou B, Zhang C, Zhong J, Fang X, Huang X, Zhang X, Xie F, Hu Q, Ge H, Yu A (2020) Ambroxol improves neuronal survival and reduces white matter damage through suppressing endoplasmic reticulum stress in microglia after intracerebral hemorrhage. Biomed Res Int 2020:8131286. https://doi.org/10.1155/2020/8131286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Muhoberac BB, Vidal R (2019) Iron, ferritin, hereditary ferritinopathy, and neurodegeneration. Front Neurosci 13:1195. https://doi.org/10.3389/fnins.2019.01195

    Article  PubMed  PubMed Central  Google Scholar 

  41. Bin JM, Harris SN, Kennedy TE (2016) The oligodendrocyte-specific antibody “CC1” binds quaking 7. J Neurochem 139(2):181–186. https://doi.org/10.1111/jnc.13745

    Article  CAS  PubMed  Google Scholar 

  42. Boggs JM (2006) Myelin basic protein: a multifunctional protein. Cell Mol Life Sci 63(17):1945–1961. https://doi.org/10.1007/s00018-006-6094-7

    Article  CAS  PubMed  Google Scholar 

  43. Guo Y, Du J, Xiao C, Xiang P, Deng Y, Hei Z, Li X (2021) Inhibition of ferroptosis-like cell death attenuates neuropathic pain reactions induced by peripheral nerve injury in rats. Eur J Pain (London, England) 25(6):1227–1240. https://doi.org/10.1002/ejp.1737

    Article  CAS  Google Scholar 

  44. Ling X, Liu D (2007) Temporal and spatial profiles of cell loss after spinal cord injury: reduction by a metalloporphyrin. J Neurosci Res 85(10):2175–2185. https://doi.org/10.1002/jnr.21362

    Article  CAS  PubMed  Google Scholar 

  45. Ek CJ, Habgood MD, Callaway JK, Dennis R, Dziegielewska KM, Johansson PA, Potter A, Wheaton B, Saunders NR (2010) Spatio-temporal progression of grey and white matter damage following contusion injury in rat spinal cord. PLoS ONE 5(8):e12021. https://doi.org/10.1371/journal.pone.0012021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang Y, Fan BY, Pang YL, Shen WY, Wang X, Zhao CX, Li WX, Liu C, Kong XH, Ning GZ, Feng SQ, Yao X (2020) Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons. Neural Regen Res 15(8):1539–1545. https://doi.org/10.4103/1673-5374.274344

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wang J, Chen Y, Chen L, Duan Y, Kuang X, Peng Z, Li C, Li Y, Xiao Y, Jin H, Tan Q, Zhang S, Zhu B, Tang Y (2020) EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats. Transl Neurosci 11(1):173–181. https://doi.org/10.1515/tnsci-2020-0119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ge MH, Tian H, Mao L, Li DY, Lin JQ, Hu HS, Huang SC, Zhang CJ, Mei XF (2021) Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway. CNS Neurosci Ther 27(9):1023–1040. https://doi.org/10.1111/cns.13657

    Article  CAS  PubMed Central  Google Scholar 

  49. Guerrero-Hue M, García-Caballero C, Palomino-Antolín A, Rubio-Navarro A, Vázquez-Carballo C, Herencia C, Martín-Sanchez D, Farré-Alins V, Egea J, Cannata P, Praga M, Ortiz A, Egido J, Sanz AB, Moreno JA (2019) Curcumin reduces renal damage associated with rhabdomyolysis by decreasing ferroptosis-mediated cell death. FASEB J 33(8):8961–8975. https://doi.org/10.1096/fj.201900077R

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by grants from the National Natural Science Foundation of China (approval no. 81471261) and Natural Science Foundation of Chongqing (approval no. cstc2018jcyjAX0080).

Author information

Author notes

  1. Hongfei Ge and Xingsen Xue have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China

    Hongfei Ge, Xingsen Xue, Jishu Xian, Linbo Yuan, Long Wang, Yongjie Zou, Jun Zhong, Zhouyang Jiang, Jiantao Shi, Tunan Chen, Hong Su, Hua Feng & Shengli Hu

  2. Department of Neurosurgery, No. 908 Hospital of People’s Liberation Army, Nanchang, 330000, Jiangxi, People’s Republic of China

    Yongjie Zou

Authors
  1. Hongfei Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xingsen Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jishu Xian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linbo Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Long Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yongjie Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhouyang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiantao Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tunan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hua Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shengli Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HFG and XSX performed most of the experiments, with assistance from JSX, LBY, YJZ, JZ, JTS, LW, ZYJ, HS, and TNC. HFG and XSX analyzed the results and edited figures. JSX, YJZ, ZYJ, and JZ performed SCI model and statistical analysis. HFG and LW performed cell culture and treatments. HFG, JTS, JW, and TNC performed immunoblotting and immunostaining. HFG wrote preliminary draft of the manuscript. SLH and HF designed experiments and revised the manuscript. All authors approved final version of the manuscript.

Corresponding authors

Correspondence to Hua Feng or Shengli Hu.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Informed Consent

Not applicable.

Research Involving Human and Animals Participants

All experiments were conducted in accordance with the China’s animal welfare legislation for the protection of animals used for scientific purposes. And all procedures were supervised by the Ethics Committee of the Southwest Hospital, Third Military Medical University for the use of laboratory animals (approval no. SYXK 20170002).

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ge, H., Xue, X., Xian, J. et al. Ferrostatin-1 Alleviates White Matter Injury Via Decreasing Ferroptosis Following Spinal Cord Injury. Mol Neurobiol 59, 161–176 (2022). https://doi.org/10.1007/s12035-021-02571-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02571-y

Keywords

Search

Navigation