• Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine (Phila Pa 1976). 2001;26:S2–12. https://doi.org/10.1097/00007632-200112151-00002.


    Google Scholar     

  • Shah M, Peterson C, Yilmaz E, Halalmeh DR, Moisi M. Current advancements in the management of spinal cord injury: A comprehensive review of literature. Surg Neurol Int. 2020;11(2). https://doi.org/10.25259/SNI_568_2019.

  • Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008;209:378–88. https://doi.org/10.1016/j.expneurol.2007.06.009.


    Google Scholar     

  • Hilton BJ, Moulson AJ, Tetzlaff W. Neuroprotection and secondary damage following spinal cord injury: concepts and methods. Neurosci Lett. 2017;652:3–10. https://doi.org/10.1016/j.neulet.2016.12.004.


    Google Scholar     

  • Scivoletto G, Tamburella F, Laurenza L, Torre M, Molinari M. Who is going to walk? A review of the factors influencing walking recovery after spinal cord injury. Front Hum Neurosci. 2014;8:141. https://doi.org/10.3389/fnhum.2014.00141.


    Google Scholar     

  • Dalkilic T, Fallah N, Noonan VK, Salimi Elizei S, Dong K, Belanger L, et al. Predicting injury severity and neurological recovery after acute cervical spinal cord injury: a comparison of cerebrospinal fluid and magnetic resonance imaging biomarkers. J Neurotrauma. 2018;35:435–45. https://doi.org/10.1089/neu.2017.5357.


    Google Scholar     

  • Losey P, Young C, Krimholtz E, Bordet R, Anthony DC. The role of hemorrhage following spinal-cord injury. Brain Res. 2014;1569:9–18. https://doi.org/10.1016/j.brainres.2014.04.033.


    Google Scholar     

  • Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke. 2003;34:2964–9. https://doi.org/10.1161/01.STR.0000103140.52838.45.


    Google Scholar     

  • Marlet JM, Jde BF, P. Experimental determination of time of intracranial hemorrhage by spectrophotometric analysis of cerebrospinal fluid. J Forensic Sci. 1982;27:880–8.


    Google Scholar     

  • Koeppen AH, Dickson AC, McEvoy JA. The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci. 1995;134:102–12. https://doi.org/10.1016/0022-510x(95)00215-n.


    Google Scholar     

  • Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, et al. Characterization of heme as activator of toll-like receptor 4. J Biol Chem. 2007;282:20221–9. https://doi.org/10.1074/jbc.M610737200.


    Google Scholar     

  • Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood. 2013;121:1276–84. https://doi.org/10.1182/blood-2012-11-451229.


    Google Scholar     

  • Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW. Haptoglobin, hemopexin, and related defense pathways—basic science, clinical perspectives, and drug development. Front Physiol. 2014;5:415. https://doi.org/10.3389/fphys.2014.00415.


    Google Scholar     

  • Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. https://doi.org/10.1016/j.cell.2012.03.042.


    Google Scholar     

  • Ryan F, Blex C, Ngo TD, Kopp MA, Michalke B, Venkataramani V, et al. Ferroptosis inhibitor improves outcome after early and delayed treatment in mild spinal cord injury. Acta Neuropathol. 2024;147:106. https://doi.org/10.1007/s00401-024-02758-2.


    Google Scholar     

  • Jhelum P, Zandee S, Ryan F, Zarruk JG, Michalke B, Venkataramani V, et al. Ferroptosis induces detrimental effects in chronic EAE and its implications for progressive MS. Acta Neuropathol Commun. 2023;11:121. https://doi.org/10.1186/s40478-023-01617-7.


    Google Scholar     

  • David S, Ryan F, Jhelum P, Kroner A. Ferroptosis Neurol Disease Neuroscientist. 2023;29:591–615. https://doi.org/10.1177/10738584221100183.


    Google Scholar     

  • Schaer CA, Deuel JW, Bittermann AG, Rubio IG, Schoedon G, Spahn DR, et al. Mechanisms of haptoglobin protection against hemoglobin peroxidation triggered endothelial damage. Cell Death Differ. 2013;20:1569–79. https://doi.org/10.1038/cdd.2013.113.


    Google Scholar     

  • Lin S, Yin Q, Zhong Q, Lv FL, Zhou Y, Li JQ, Wang JZ, Su BY, Yang QW. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J Neuroinflammation. 2012;9:46. https://doi.org/10.1186/1742-2094-9-46.


    Google Scholar     

  • Vallelian F, Deuel JW, Opitz L, Schaer CA, Puglia M, Lonn M, et al. Proteasome inhibition and oxidative reactions disrupt cellular homeostasis during heme stress. Cell Death Differ. 2015;22:597–611. https://doi.org/10.1038/cdd.2014.154.


    Google Scholar     

  • Zhao X, Sun G, Zhang J, Strong R, Dash PK, Kan YW, et al. Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke. 2007;38:3280–6. https://doi.org/10.1161/STROKEAHA.107.486506.


    Google Scholar     

  • Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW, et al. Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med. 2007;43:408–14. https://doi.org/10.1016/j.freeradbiomed.2007.04.020.


    Google Scholar     

  • Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK. Identification of the receptor scavenging hemopexin-heme complexes. Blood. 2005;106:2572–9. https://doi.org/10.1182/blood-2005-03-1185.


    Google Scholar     

  • Shih AW, McFarlane A, Verhovsek H. Haptoglobin testing in hemolysis: measurement and interpretation. Am J Hematol. 2014;89:443–7. https://doi.org/10.1002/ajh.23623.


    Google Scholar     

  • Galea J, Cruickshank G, Teeling JL, Boche D, Garland P, Perry VH, et al. The intrathecal CD163-haptoglobin-hemoglobin scavenging system in subarachnoid hemorrhage. J Neurochem. 2012;121:785–92. https://doi.org/10.1111/j.1471-4159.2012.07716.x.


    Google Scholar     

  • Zhao X, Song S, Sun G, Strong R, Zhang J, Grotta JC, et al. Neuroprotective role of haptoglobin after intracerebral hemorrhage. J Neurosci. 2009;29:15819–27. https://doi.org/10.1523/JNEUROSCI.3776-09.2009.


    Google Scholar     

  • Chen L, Zhang X, Chen-Roetling J, Regan RF. Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice. J Neurosurg. 2011;114:1159–67. https://doi.org/10.3171/2010.10.JNS10861.


    Google Scholar     

  • Ma B, Day JP, Phillips H, Slootsky B, Tolosano E, Dore S. Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage. J Neuroinflammation. 2016;13:26. https://doi.org/10.1186/s12974-016-0490-1.


    Google Scholar     

  • Hahl P, Davis T, Washburn C, Rogers JT, Smith A. Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states. J Neurochem. 2013;125:89–101. https://doi.org/10.1111/jnc.12165.


    Google Scholar     

  • Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18:e3000410. https://doi.org/10.1371/journal.pbio.3000410.


    Google Scholar     

  • Tolosano E, Hirsch E, Patrucco E, Camaschella C, Navone R, Silengo L, et al. Defective recovery and severe renal damage after acute hemolysis in hemopexin-deficient mice. Blood. 1999;94:3906–14.


    Google Scholar     

  • Metz GA, Whishaw IQ. Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore- and hindlimb stepping, placing, and co-ordination. J Neurosci Methods. 2002;115:169–79.


    Google Scholar     

  • Pelisch N, Almanza R, Stehlik J, Aperi KE, B.V., and, Kroner A. CCL3 contributes to secondary damage after spinal cord injury. J Neuroinflammation. 2020;17:362. https://doi.org/10.1186/s12974-020-02037-3.


    Google Scholar     

  • Pelisch N, Almanza JR, Stehlik KE, Aperi BV, Kroner A. Use of a Self-Delivering Anti-CCL3 FANA Oligonucleotide as an Innovative Approach to Target Inflammation after Spinal Cord Injury. Eneuro 8. Artn. 2021;0338-20.2021. https://doi.org/10.1523/eneuro.0338-20.2021.

  • Kigerl KA, McGaughy VM, Popovich PG. Comparative analysis of lesion development and intraspinal inflammation in four strains of mice following spinal contusion injury. J Comp Neurol. 2006;494:578–94. https://doi.org/10.1002/cne.20827.


    Google Scholar     

  • Tolosano E, Fagoonee S, Morello N, Vinchi F, Fiorito V. Heme scavenging and the other facets of hemopexin. Antioxid Redox Signal. 2010;12:305–20. https://doi.org/10.1089/ars.2009.2787.


    Google Scholar     

  • Greenhalgh AD, David S. Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death. J Neurosci. 2014;34:6316–22. https://doi.org/10.1523/JNEUROSCI.4912-13.2014.


    Google Scholar     

  • Brennan FH, Li Y, Wang C, Ma A, Guo Q, Li Y, et al. Microglia coordinate cellular interactions during spinal cord repair in mice. Nat Commun. 2022;13:4096. https://doi.org/10.1038/s41467-022-31797-0.


    Google Scholar     

  • Morizawa YM, Hirayama Y, Ohno N, Shibata S, Shigetomi E, Sui Y, et al. Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun. 2017;8:28. https://doi.org/10.1038/s41467-017-00037-1.


    Google Scholar     

  • Kwiecien JM, Dabrowski W, Dabrowska-Bouta B, Sulkowski G, Oakden W, Kwiecien-Delaney CJ, Yaron JR, Zhang L, Schutz L, Marzec-Kotarska B, Stanisz GJ, et al. Prolonged inflammation leads to ongoing damage after spinal cord injury. PLoS ONE. 2020;15:e0226584. https://doi.org/10.1371/journal.pone.0226584.


    Google Scholar     

  • Turtle JD, Henwood MK, Strain MM, Huang YJ, Miranda RC, Grau JW. Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury. Exp Neurol. 2019;311:115–24. https://doi.org/10.1016/j.expneurol.2018.09.018.


    Google Scholar     

  • Ahuja CS, Wilson JR, Nori S, Kotter MRN, Druschel C, Curt A, et al. Traumatic spinal cord injury. Nat Rev Dis Primers. 2017;3:17018. https://doi.org/10.1038/nrdp.2017.18.


    Google Scholar     

  • Kroner A, Greenhalgh AD, Zarruk JG, Passos Dos Santos R, Gaestel M, David S. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron. 2014;83:1098–116. https://doi.org/10.1016/j.neuron.2014.07.027.


    Google Scholar     

  • Einwachter H, Heiseke A, Schlitzer A, Gasteiger G, Adler H, Voehringer D, et al. The innate immune response to infection induces Erythropoietin-dependent replenishment of the dendritic cell compartment. Front Immunol. 2020;11:1627. https://doi.org/10.3389/fimmu.2020.01627.


    Google Scholar     

  • David S, Kroner A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci. 2011;12:388–99. https://doi.org/10.1038/nrn3053.


    Google Scholar     

  • Timmins GS, Davies MJ, Song DX, Muller-Eberhard U. EPR studies on the effects of complexation of heme by hemopexin upon its reactions with organic peroxides. Free Radic Res. 1995;23:559–69. https://doi.org/10.3109/10715769509065277.


    Google Scholar     

  • Stephen R, Robinson TND, Ralf, Dringen, Glenda M, Bishop. Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke. Redox Rep. 2013;228–35. https://doi.org/10.1179/135100009X12525712409931.

  • Smith JMGaA. Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation. Biochem J. 1988;861–5. https://doi.org/10.1042/bj2560861.

  • Styliani H, Vincent RWG, Nurith Shaklai JMS, Ursula Muller-Eberhard. The influence of heme-binding proteins in heme-catalyzed oxidations. Arch Biochem Biophys. 1988;265:539–50.


    Google Scholar     

  • Li RC, Saleem S, Zhen G, Cao W, Zhuang H, Lee J, et al. Heme-hemopexin complex attenuates neuronal cell death and stroke damage. J Cereb Blood Flow Metab. 2009;29(5):953–64. https://doi.org/10.1038/jcbfm.2009.19.


    Google Scholar     

  • Tolosano E, Patrucco HE, Camaschella E, Navone C, Silengo R, Altruda L. F. Defective recovery and severe renal damage after acute hemolysis in hemopexin-deficient mice blood. 1999.

  • Lim YK, Jenner A, Ali AB, Wang Y, Hsu SI, Chong SM, et al. Haptoglobin reduces renal oxidative DNA and tissue damage during phenylhydrazine-induced hemolysis. Kidney Int. 2000;58:1033–44. https://doi.org/10.1046/j.1523-1755.2000.00261.x.


    Google Scholar     

  • Yalamanoglu A, Deuel JW, Hunt RC, Baek JH, Hassell K, Redinius K, Irwin DC, Schaer DJ, Buehler PW. Depletion of haptoglobin and hemopexin promote hemoglobin-mediated lipoprotein oxidation in sickle cell disease. Am J Physiol Lung Cell Mol Physiol. 2018;315:L765–74. https://doi.org/10.1152/ajplung.00269.2018.


    Google Scholar     

  • Chen-Roetling J, Li Y, Cao Y, Yan Z, Lu X, Regan RF. Effect of hemopexin treatment on outcome after intracerebral hemorrhage in mice. Brain Res. 2021;1765:147507. https://doi.org/10.1016/j.brainres.2021.147507.


    Google Scholar     

  • Galea I, Bandyopadhyay S, Bulters D, Humar R, Hugelshofer M, Schaer DJ, et al. Haptoglobin treatment for aneurysmal subarachnoid hemorrhage: review and expert consensus on clinical translation. Stroke. 2023;54:1930–42. https://doi.org/10.1161/STROKEAHA.123.040205.


    Google Scholar     

  • Han D, Yu Z, Liu W, Yin D, Pu Y, Feng J, et al. Plasma hemopexin ameliorates murine spinal cord injury by switching microglia from the M1 state to the M2 state. Cell Death Dis. 2018;9:181. https://doi.org/10.1038/s41419-017-0236-8.


    Google Scholar     

  • Jaeschke A, Hui DY. LDL receptor-related protein 1 and its interacting partners in tissue homeostasis. Curr Opin Lipidol. 2021;32:301–7. https://doi.org/10.1097/MOL.0000000000000776.


    Google Scholar     

  • Dong B, Cai M, Fang Z, Wei H, Zhu F, Li G, et al. Hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia. BMC Neurosci. 2013;14:58. https://doi.org/10.1186/1471-2202-14-58.


    Google Scholar     

  • Karnup S, Hashimoto M, Cho KJ, Beckel J, de Groat W, Yoshimura N. Sexual dimorphism of spinal neural circuits controlling the mouse external urethral sphincter with and without spinal cord injury. J Comp Neurol. 2024;532:e25658. https://doi.org/10.1002/cne.25658.


    Google Scholar     

  • Ide S, Ide K, Abe K, Kobayashi Y, Kitai H, McKey J, et al. Sex differences in resilience to ferroptosis underlie sexual dimorphism in kidney injury and repair. Cell Rep. 2022;41(6):111610. https://doi.org/10.1016/j.celrep.2022.111610.


    Google Scholar     

  • Tao H, Dar HY, Tian C, Banerjee S, Glazer ES, Srinivasan S, et al. Differences in hepatocellular iron metabolism underlie sexual dimorphism in hepatocyte ferroptosis. Redox Biol. 2023;67:102892. https://doi.org/10.1016/j.redox.2023.102892.


    Google Scholar     

  • Toth B, Yokoyama Y, Kuebler JF, Schwacha MG, Rue LW 3rd, Bland KI, Chaudry IH. Sex differences in hepatic Heme Oxygenase expression and activity following trauma and hemorrhagic shock. Arch Surg. 2003;138:1375–82. https://doi.org/10.1001/archsurg.138.12.1375.


    Google Scholar     

  • Kapojos JJ, van den Berg A, van Goor H, te Loo MW, Poelstra K, Borghuis T, Bakker WW. Production of hemopexin by TNF-alpha stimulated human mesangial cells. Kidney Int. 2003;63:1681–6. https://doi.org/10.1046/j.1523-1755.2003.00907.x.


    Google Scholar     

  • Tolosano E, Altruda F. Hemopexin: structure, function, and regulation. DNA Cell Biol. 2002;21:297–306. https://doi.org/10.1089/104454902753759717.


    Google Scholar     

  • Novrup HG, Bracchi-Ricard V, Ellman DG, Ricard J, Jain A, Runko E, Lyck L, Yli-Karjanmaa M, Szymkowski DE, Pearse DD, Lambertsen KL, et al. Central but not systemic administration of XPro1595 is therapeutic following moderate spinal cord injury in mice. J Neuroinflammation. 2014;11:159. https://doi.org/10.1186/s12974-014-0159-6.


    Google Scholar     

  • Gerald MJ, Bracchi-Ricard V, Ricard J, Fischer R, Nandakumar B, Blumenthal GH, et al. Continuous infusion of an agonist of the tumor necrosis factor receptor 2 in the spinal cord improves recovery after traumatic contusive injury. CNS Neurosci Ther. 2019;25:884–93. https://doi.org/10.1111/cns.13125.


    Google Scholar     

  • Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004;24:2143–55. https://doi.org/10.1523/JNEUROSCI.3547-03.2004.


    Google Scholar     

  • 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. https://doi.org/10.1186/s12974-014-0150-2.


    Google Scholar     

  • Stirling DP, Liu S, Kubes P, Yong VW. Depletion of Ly6G/Gr-1 leukocytes after spinal cord injury in mice alters wound healing and worsens neurological outcome. J Neurosci. 2009;29:753–64.


    Google Scholar     

  • Pacheco MR, Tran AV, Bradley ML, Leal-Garcia ME, Ozturgut M, Barnett EA, Chakka VV, Devaraj S, Kirchhoff M, Mulamba T, Thomas K, et al. Mature neutrophils promotelong-term functional recovery after spinal cord injury in a sex-dependent manner.BioRxiv. 2025;202520022025640256. https://doi.org/10.1101/2025.02.25.640256.

  • Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci. 2001;21:4183–7.

  • Castellani RJ, Perry G, Siedlak SL, Nunomura A, Shimohama S, Zhang J, et al.Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem lewy bodies in humans. Neurosci Lett. 2002;319:25–8. https://doi.org/10.1016/s0304-3940(01)02514-9.

  • Ma T, Du J, Zhang Y, Wang Y, Wang B, Zhang T. Gpx4-independent ferroptosis-a new strategy in disease’s therapy. Cell Death Discov. 2022;8:434. https://doi.org/10.1038/s41420-022-01212-0.

  • Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, and Popovich PG. Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma 23, 2006;635–659. https://doi.org/10.1089/neu.2006.23.635.