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Protein Degradome of Spinal Cord Injury: Biomarkers and Potential Therapeutic Targets

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Abstract

Degradomics is a proteomics sub-discipline whose goal is to identify and characterize protease-substrate repertoires. With the aim of deciphering and characterizing key signature breakdown products, degradomics emerged to define encryptic biomarker neoproteins specific to certain disease processes. Remarkable improvements in structural and analytical experimental methodologies as evident in research investigating cellular behavior in neuroscience and cancer have allowed the identification of specific degradomes, increasing our knowledge about proteases and their regulators and substrates along with their implications in health and disease. A physiologic balance between protein synthesis and degradation is sought with the activation of proteolytic enzymes such as calpains, caspases, cathepsins, and matrix metalloproteinases. Proteolysis is essential for development, growth, and regeneration; however, inappropriate and uncontrolled activation of the proteolytic system renders the diseased tissue susceptible to further neurotoxic processes. In this article, we aim to review the protease-substrate repertoires as well as emerging therapeutic interventions in spinal cord injury at the degradomic level. Several protease substrates and their breakdown products, essential for the neuronal structural integrity and functional capacity, have been characterized in neurotrauma including cytoskeletal proteins, neuronal extracellular matrix glycoproteins, cell junction proteins, and ion channels. Therefore, targeting exaggerated protease activity provides a potentially effective therapeutic approach in the management of protease-mediated neurotoxicity in reducing the extent of damage secondary to spinal cord injury.

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References

  1. Overall CM, Dean RA (2006) Degradomics: systems biology of the protease web. Pleiotropic roles of MMPs in cancer. Cancer Metastasis Rev 25(1):69–75. https://doi.org/10.1007/s10555-006-7890-0

    Article  PubMed  Google Scholar 

  2. Lopez-Otin C, Overall CM (2002) Protease degradomics: a new challenge for proteomics. Nat Rev Mol Cell Biol 3(7):509–519. https://doi.org/10.1038/nrm858

    Article  CAS  PubMed  Google Scholar 

  3. Savickas S, Keller UAD (2017) Targeted degradomics in protein terminomics and protease substrate discovery. Biol Chem. https://doi.org/10.1515/hsz-2017-0187

    PubMed  Google Scholar 

  4. Sarkis GA, Mangaonkar MD, Moghieb A, Lelling B, Guertin M, Yadikar H, Yang Z, Kobeissy F et al (2017) The application of proteomics to traumatic brain and spinal cord injuries. Curr Neurol Neurosci Rep 17(3):23. https://doi.org/10.1007/s11910-017-0736-z

    Article  CAS  PubMed  Google Scholar 

  5. Abou-El-Hassan H, Sukhon F, Assaf EJ, Bahmad H, Abou-Abbass H, Jourdi H, Kobeissy FH (2017) Degradomics in neurotrauma: profiling traumatic brain injury. Methods Mol Biol 1598:65–99. https://doi.org/10.1007/978-1-4939-6952-4_4

    Article  CAS  PubMed  Google Scholar 

  6. El-Assaad A, Dawy Z, Nemer G, Hajj H, Kobeissy FH (2017) Efficient and accurate algorithm for cleaved fragments prediction (CFPA) in protein sequences dataset based on consensus and its variants: a novel degradomics prediction application. Methods Mol Biol 1598:329–352. https://doi.org/10.1007/978-1-4939-6952-4_17

    Article  CAS  PubMed  Google Scholar 

  7. Quanico J, Franck J, Wisztorski M, Salzet M, Fournier I (2017) Combined MALDI Mass spectrometry imaging and parafilm-assisted microdissection-based LC-MS/MS workflows in the study of the brain. Methods Mol Biol 1598:269–283. https://doi.org/10.1007/978-1-4939-6952-4_13

    Article  CAS  PubMed  Google Scholar 

  8. Ropper AE, Ropper AH (2017) Acute spinal cord compression. N Engl J Med 376(14):1358–1369. https://doi.org/10.1056/NEJMra1516539

    Article  PubMed  Google Scholar 

  9. David WS, Bowley MP, Mehan WA Jr, Shin JH, Gerstner ER, DeWitt JC (2017) Case 19-2017 - a 53-Year-old woman with leg numbness and weakness. N Engl J Med 376(25):2471–2481. https://doi.org/10.1056/NEJMcpc1701762

    Article  PubMed  Google Scholar 

  10. Snyder EY, Teng YD (2012) Stem cells and spinal cord repair. N Engl J Med 366(20):1940–1942. https://doi.org/10.1056/NEJMcibr1200138

    Article  CAS  PubMed  Google Scholar 

  11. Injury GBDTB, Spinal Cord Injury C (2019) Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18(1):56–87. https://doi.org/10.1016/S1474-4422(18)30415-0

    Article  Google Scholar 

  12. Ackery A, Tator C, Krassioukov A (2004) A global perspective on spinal cord injury epidemiology. J Neurotrauma 21(10):1355–1370. https://doi.org/10.1089/neu.2004.21.1355

    Article  PubMed  Google Scholar 

  13. Abou-Abbass H, Bahmad H, Abou-El-Hassan H, Zhu R, Zhou S, Dong X, Hamade E, Mallah K et al (2016) Deciphering glycomics and neuroproteomic alterations in experimental traumatic brain injury: comparative analysis of aspirin and clopidogrel treatment. Electrophoresis 37(11):1562–1576. https://doi.org/10.1002/elps.201500583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Abou-El-Hassan H, Dia B, Choucair K, Eid SA, Najdi F, Baki L, Talih F, Eid AA et al (2017) Traumatic brain injury, diabetic neuropathy and altered-psychiatric health: the fateful triangle. Med Hypotheses 108:69–80. https://doi.org/10.1016/j.mehy.2017.08.008

    Article  PubMed  Google Scholar 

  15. McKinley W, Santos K, Meade M, Brooke K (2007) Incidence and outcomes of spinal cord injury clinical syndromes. J Spinal Cord Med 30(3):215–224

    PubMed  PubMed Central  Google Scholar 

  16. Tator CH, Fehlings MG (1991) Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg 75(1):15–26. https://doi.org/10.3171/jns.1991.75.1.0015

    Article  CAS  PubMed  Google Scholar 

  17. Nasser M, Bejjani F, Raad M, Abou-El-Hassan H, Mantash S, Nokkari A, Ramadan N, Kassem N et al (2016) Traumatic brain injury and blood-brain barrier cross-talk. CNS Neurol Disord Drug Targets 15(9):1030–1044

    CAS  PubMed  Google Scholar 

  18. Arevalo-Martin A, Grassner L, Garcia-Ovejero D, Paniagua-Torija B, Barroso-Garcia G, Arandilla AG, Mach O, Turrero A et al (2018) Elevated autoantibodies in subacute human spinal cord injury are naturally occurring antibodies. Front Immunol 9:2365. https://doi.org/10.3389/fimmu.2018.02365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kwo S, Young W, Decrescito V (1989) Spinal cord sodium, potassium, calcium, and water concentration changes in rats after graded contusion injury. J Neurotrauma 6(1):13–24. https://doi.org/10.1089/neu.1989.6.13

    Article  CAS  PubMed  Google Scholar 

  20. Hall ED, Braughler JM (1993) Free radicals in CNS injury. Res Publ Assoc Res Nerv Ment Dis 71:81–105

    CAS  PubMed  Google Scholar 

  21. Veeravalli KK, Dasari VR, Rao JS (2012) Regulation of proteases after spinal cord injury. J Neurotrauma 29(13):2251–2262. https://doi.org/10.1089/neu.2012.2460

    Article  PubMed  Google Scholar 

  22. Grant RA, Quon JL, Abbed KM (2015) Management of acute traumatic spinal cord injury. Curr Treat Options Neurol 17(2):334. https://doi.org/10.1007/s11940-014-0334-1

    Article  PubMed  Google Scholar 

  23. McKinley WO, Tewksbury MA, Mujteba NM (2002) Spinal stenosis vs traumatic spinal cord injury: a rehabilitation outcome comparison. J Spinal Cord Med 25(1):28–32

    PubMed  Google Scholar 

  24. McDonald JW, Sadowsky C (2002) Spinal-cord injury. Lancet 359(9304):417–425. https://doi.org/10.1016/S0140-6736(02)07603-1

    Article  PubMed  Google Scholar 

  25. del Mar N, von Buttlar X, Yu AS, Guley NH, Reiner A, Honig MG (2015) A novel closed-body model of spinal cord injury caused by high-pressure air blasts produces extensive axonal injury and motor impairments. Exp Neurol 271:53–71. https://doi.org/10.1016/j.expneurol.2015.04.023

    Article  PubMed  PubMed Central  Google Scholar 

  26. Trivedi A, Olivas AD, Noble-Haeusslein LJ (2006) Inflammation and spinal cord injury: infiltrating leukocytes as determinants of injury and repair processes. Clin Neurosci Res 6(5):283–292. https://doi.org/10.1016/j.cnr.2006.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Martin JB (1999) Molecular basis of the neurodegenerative disorders. N Engl J Med 340(25):1970–1980. https://doi.org/10.1056/NEJM199906243402507

    Article  CAS  PubMed  Google Scholar 

  28. Gill LC, Ross HH, Lee KZ, Gonzalez-Rothi EJ, Dougherty BJ, Judge AR, Fuller DD (2014) Rapid diaphragm atrophy following cervical spinal cord hemisection. Respir Physiol Neurobiol 192:66–73. https://doi.org/10.1016/j.resp.2013.12.006

    Article  CAS  PubMed  Google Scholar 

  29. Banik NL, Shields DC, Ray S, Davis B, Matzelle D, Wilford G, Hogan EL (1998) Role of calpain in spinal cord injury: effects of calpain and free radical inhibitors(a). Ann N Y Acad Sci 844(1):131–137. https://doi.org/10.1111/j.1749-6632.1998.tb08228.x

    Article  CAS  PubMed  Google Scholar 

  30. Supinski GS, Wang W, Callahan LA (2009) Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness. J Appl Physiol 107(5):1389–1396. https://doi.org/10.1152/japplphysiol.00341.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ray SK, Samantaray S, Smith JA, Matzelle DD, Das A, Banik NL (2011) Inhibition of cysteine proteases in acute and chronic spinal cord injury. Neurotherapeutics 8(2):180–186. https://doi.org/10.1007/s13311-011-0037-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ellis RC, O'Steen WA, Hayes RL, Nick HS, Wang KK, Anderson DK (2005) Cellular localization and enzymatic activity of cathepsin B after spinal cord injury in the rat. Exp Neurol 193(1):19–28. https://doi.org/10.1016/j.expneurol.2004.11.034

    Article  CAS  PubMed  Google Scholar 

  33. Moghieb A, Bramlett HM, Das JH, Yang Z, Selig T, Yost RA, Wang MS, Dietrich WD et al (2016) Differential neuroproteomic and systems biology analysis of spinal cord injury. Molec Cell Proteom: MCP 15(7):2379–2395. https://doi.org/10.1074/mcp.M116.058115

    CAS  Google Scholar 

  34. Moon C, Lee TK, Kim H, Ahn M, Lee Y, Kim MD, Sim KB, Shin T (2008) Immunohistochemical study of cathepsin D in the spinal cords of rats with clip compression injury. J Vet Med Sci 70(9):937–941

    CAS  PubMed  Google Scholar 

  35. Ellis RC, Earnhardt JN, Hayes RL, Wang KK, Anderson DK (2004) Cathepsin B mRNA and protein expression following contusion spinal cord injury in rats. J Neurochem 88(3):689–697

    CAS  PubMed  Google Scholar 

  36. Hashimoto M, Koda M, Ino H, Yoshinaga K, Murata A, Yamazaki M, Kojima K, Chiba K et al (2005) Gene expression profiling of cathepsin D, metallothioneins-1 and -2, osteopontin, and tenascin-C in a mouse spinal cord injury model by cDNA microarray analysis. Acta Neuropathol 109(2):165–180. https://doi.org/10.1007/s00401-004-0926-z

    Article  CAS  PubMed  Google Scholar 

  37. Kanno H, Ozawa H, Sekiguchi A, Itoi E (2009) The role of autophagy in spinal cord injury. Autophagy 5(3):390–392

    CAS  PubMed  Google Scholar 

  38. Liu S, Sarkar C, Dinizo M, Faden AI, Koh EY, Lipinski MM, Wu J (2015) Disrupted autophagy after spinal cord injury is associated with ER stress and neuronal cell death. Cell Death Dis 6:e1582. https://doi.org/10.1038/cddis.2014.527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang YH, Belegu V, Zou Y, Wang F, Qian BJ, Liu R, Dai P, Zhao W et al (2015) Endoplasmic reticulum protein 29 protects axotomized neurons from apoptosis and promotes neuronal regeneration associated with Erk signal. Mol Neurobiol 52(1):522–532. https://doi.org/10.1007/s12035-014-8840-4

    Article  CAS  PubMed  Google Scholar 

  40. Fu Q, Zhou Z, Li X, Guo H, Fan X, Chen J, Zhuang J, Zheng S et al (2014) Protective effect of adenosine preconditioning against spinal cord ischemia-reperfusion injury in rats. Nan fang yi ke da xue xue bao = J South Med Univ 34(1):92–95

    CAS  Google Scholar 

  41. Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274(31):21491–21494

    CAS  PubMed  Google Scholar 

  42. Rundhaug JE (2005) Matrix metalloproteinases and angiogenesis. J Cell Mol Med 9(2):267–285

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Buss A, Pech K, Kakulas BA, Martin D, Schoenen J, Noth J, Brook GA (2007) Matrix metalloproteinases and their inhibitors in human traumatic spinal cord injury. BMC Neurol 7:17

    PubMed  PubMed Central  Google Scholar 

  44. Zhou Y, Cui Z, Xia X, Liu C, Zhu X, Cao J, Wu Y, Zhou L et al (2014) Matrix metalloproteinase-1 (MMP-1) expression in rat spinal cord injury model. Cell Mol Neurobiol 34(8):1151–1163. https://doi.org/10.1007/s10571-014-0090-5

    Article  CAS  PubMed  Google Scholar 

  45. Goussev S, Hsu JY, Lin Y, Tjoa T, Maida N, Werb Z, Noble-Haeusslein LJ (2003) Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing. J Neurosurg 99(2 Suppl):188–197

    CAS  PubMed  PubMed Central  Google Scholar 

  46. de Castro RC, Jr., Burns CL, McAdoo DJ, Romanic AM (2000) Metalloproteinase increases in the injured rat spinal cord. Neuroreport 11 (16):3551–3554

    CAS  PubMed  Google Scholar 

  47. Veeravalli KK, Dasari VR, Tsung AJ, Dinh DH, Gujrati M, Fassett D, Rao JS (2009) Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury. Neurobiol Dis 36(1):200–212

    CAS  PubMed  Google Scholar 

  48. Bock P, Spitzbarth I, Haist V, Stein VM, Tipold A, Puff C, Beineke A, Baumgartner W (2013) Spatio-temporal development of axonopathy in canine intervertebral disc disease as a translational large animal model for nonexperimental spinal cord injury. Brain Pathol 23(1):82–99

    CAS  PubMed  Google Scholar 

  49. Duchossoy Y, Horvat JC, Stettler O (2001) MMP-related gelatinase activity is strongly induced in scar tissue of injured adult spinal cord and forms pathways for ingrowing neurites. Mol Cell Neurosci 17(6):945–956

    CAS  PubMed  Google Scholar 

  50. Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22(17):7526–7535

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wells JE, Rice TK, Nuttall RK, Edwards DR, Zekki H, Rivest S, Yong VW (2003) An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J Neurosci 23(31):10107–10115

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Anik I, Kokturk S, Genc H, Cabuk B, Koc K, Yavuz S, Ceylan S, Ceylan S et al (2011) Immunohistochemical analysis of TIMP-2 and collagen types I and IV in experimental spinal cord ischemia-reperfusion injury in rats. J Spinal Cord Med 34(3):257–264. https://doi.org/10.1179/107902611X12972448729648

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yu F, Kamada H, Niizuma K, Endo H, Chan PH (2008) Induction of mmp-9 expression and endothelial injury by oxidative stress after spinal cord injury. J Neurotrauma 25(3):184–195. https://doi.org/10.1089/neu.2007.0438

    Article  PubMed  PubMed Central  Google Scholar 

  54. Zou J, Wang YX, Mu HJ, Xiang J, Wu W, Zhang B, Xie P (2011) Down-regulation of glutamine synthetase enhances migration of rat astrocytes after in vitro injury. Neurochem Int 58(3):404–413. https://doi.org/10.1016/j.neuint.2010.12.018

    Article  CAS  PubMed  Google Scholar 

  55. Chen J, Herrup K (2012) Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress. PLoS One 7(3):e33177. https://doi.org/10.1371/journal.pone.0033177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gorovits R, Avidan N, Avisar N, Shaked I, Vardimon L (1997) Glutamine synthetase protects against neuronal degeneration in injured retinal tissue. Proc Natl Acad Sci U S A 94(13):7024–7029

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Benton RL, Ross CD, Miller KE (2000) Glutamine synthetase activities in spinal white and gray matter 7 days following spinal cord injury in rats. Neurosci Lett 291(1):1–4

    CAS  PubMed  Google Scholar 

  58. Liu C, Wu W, Zhang B, Xiang J, Zou J (2013) Temporospatial expression and cellular localization of glutamine synthetase following traumatic spinal cord injury in adult rats. Mol Med Rep 7(5):1431–1436. https://doi.org/10.3892/mmr.2013.1383

    Article  CAS  PubMed  Google Scholar 

  59. Seeds N, Mikesell S, Vest R, Bugge T, Schaller K, Minor K (2011) Plasminogen activator promotes recovery following spinal cord injury. Cell Mol Neurobiol 31(6):961–967. https://doi.org/10.1007/s10571-011-9701-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li Z, Liu F, Zhang L, Cao Y, Shao Y, Wang X, Jiang X, Chen Z (2018) Neuroserpin restores autophagy and promotes functional recovery after acute spinal cord injury in rats. Mol Med Rep 17(2):2957–2963. https://doi.org/10.3892/mmr.2017.8249

    Article  CAS  PubMed  Google Scholar 

  61. Terayama R, Bando Y, Murakami K, Kato K, Kishibe M, Yoshida S (2007) Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury. Neuroscience 148(1):175–187. https://doi.org/10.1016/j.neuroscience.2007.05.037

    Article  CAS  PubMed  Google Scholar 

  62. Paterniti I, Genovese T, Mazzon E, Crisafulli C, Di Paola R, Galuppo M, Bramanti P, Cuzzocrea S (2010) Liver X receptor agonist treatment regulates inflammatory response after spinal cord trauma. J Neurochem 112(3):611–624. https://doi.org/10.1111/j.1471-4159.2009.06471.x

    Article  CAS  PubMed  Google Scholar 

  63. Gong B, Radulovic M, Figueiredo-Pereira ME, Cardozo C (2016) The ubiquitin-proteasome system: potential therapeutic targets for Alzheimer’s disease and spinal cord injury. Front Mol Neurosci 9:4. https://doi.org/10.3389/fnmol.2016.00004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Chen A, McEwen ML, Sun S, Ravikumar R, Springer JE (2010) Proteomic and phosphoproteomic analyses of the soluble fraction following acute spinal cord contusion in rats. J Neurotrauma 27(1):263–274. https://doi.org/10.1089/neu.2009.1051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen A, Sun S, Ravikumar R, Visavadiya NP, Springer JE (2013) Differential proteomic analysis of acute contusive spinal cord injury in rats using iTRAQ reagent labeling and LC-MS/MS. Neurochem Res 38(11):2247–2255. https://doi.org/10.1007/s11064-013-1132-y

    Article  CAS  PubMed  Google Scholar 

  66. Sakurai M, Ayukawa K, Setsuie R, Nishikawa K, Hara Y, Ohashi H, Nishimoto M, Abe T et al (2006) Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation. J Cell Sci 119(Pt 1):162–171. https://doi.org/10.1242/jcs.02716

    Article  CAS  PubMed  Google Scholar 

  67. Jiang X, Yu M, Ou Y, Cao Y, Yao Y, Cai P, Zhang F (2017) Downregulation of USP4 promotes activation of microglia and subsequent neuronal inflammation in rat spinal cord after injury. Neurochem Res 42(11):3245–3253. https://doi.org/10.1007/s11064-017-2361-2

    Article  CAS  PubMed  Google Scholar 

  68. Chen X, Liu L, Qian R, Liu J, Yao Y, Jiang Z, Song X, Ren J et al (2017) Expression of Sam68 associates with neuronal apoptosis and reactive astrocytes after spinal cord injury. Cell Mol Neurobiol 37(3):487–498. https://doi.org/10.1007/s10571-016-0384-x

    Article  CAS  PubMed  Google Scholar 

  69. Wei H, Teng H, Huan W, Zhang S, Fu H, Chen F, Wang J, Wu C et al (2012) An upregulation of SENP3 after spinal cord injury: implications for neuronal apoptosis. Neurochem Res 37(12):2758–2766. https://doi.org/10.1007/s11064-012-0869-z

    Article  CAS  PubMed  Google Scholar 

  70. Pei JP, Fan LH, Nan K, Li J, Dang XQ, Wang KZ (2017) HSYA alleviates secondary neuronal death through attenuating oxidative stress, inflammatory response, and neural apoptosis in SD rat spinal cord compression injury. J Neuroinflammation 14(1):97. https://doi.org/10.1186/s12974-017-0870-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ma L, Shen YQ, Khatri HP, Schachner M (2014) The asparaginyl endopeptidase legumain is essential for functional recovery after spinal cord injury in adult zebrafish. PLoS One 9(4):e95098. https://doi.org/10.1371/journal.pone.0095098

    Article  PubMed  PubMed Central  Google Scholar 

  72. Squair JW, DeVeau KM, Harman KA, Poormasjedi-Meibod MS, Hayes B, Liu J, Magnuson DSK, Krassioukov AV et al (2018) Spinal cord injury causes systolic dysfunction and cardiomyocyte atrophy. J Neurotrauma 35(3):424–434. https://doi.org/10.1089/neu.2017.4984

    Article  PubMed  Google Scholar 

  73. Poormasjedi-Meibod MS, Mansouri M, Fossey M, Squair JW, Liu J, McNeill JH, West CR (2018) Experimental spinal cord injury causes left-ventricular atrophy and is associated with an upregulation of proteolytic pathways. J Neurotrauma. https://doi.org/10.1089/neu.2017.5624

    PubMed  Google Scholar 

  74. Myeku N, Wang H, Figueiredo-Pereira ME (2012) cAMP stimulates the ubiquitin/proteasome pathway in rat spinal cord neurons. Neurosci Lett 527(2):126–131. https://doi.org/10.1016/j.neulet.2012.08.051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tica J, Bradbury EJ, Didangelos A (2018) Combined transcriptomics, proteomics and bioinformatics identify drug targets in spinal cord injury. Int J Mol Sci 19(5). https://doi.org/10.3390/ijms19051461

    PubMed Central  Google Scholar 

  76. Murphy MP, LeVine H 3rd (2010) Alzheimer’s disease and the amyloid-beta peptide. J Alzheimer’s Dis: JAD 19(1):311–323. https://doi.org/10.3233/JAD-2010-1221

    Article  CAS  Google Scholar 

  77. Kobayashi S, Sasaki T, Katayama T, Hasegawa T, Nagano A, Sato K (2010) Temporal-spatial expression of presenilin 1 and the production of amyloid-beta after acute spinal cord injury in adult rat. Neurochem Int 56(3):387–393. https://doi.org/10.1016/j.neuint.2009.11.005

    Article  CAS  PubMed  Google Scholar 

  78. Sharma HS, Muresanu DF, Lafuente JV, Sjoquist PO, Patnaik R, Sharma A (2015) Nanoparticles exacerbate both ubiquitin and heat shock protein expressions in spinal cord injury: neuroprotective effects of the proteasome inhibitor carfilzomib and the antioxidant compound H-290/51. Mol Neurobiol 52(2):882–898. https://doi.org/10.1007/s12035-015-9297-9

    Article  CAS  PubMed  Google Scholar 

  79. Ghasemlou N, Bouhy D, Yang J, Lopez-Vales R, Haber M, Thuraisingam T, He G, Radzioch D et al (2010) Beneficial effects of secretory leukocyte protease inhibitor after spinal cord injury. Brain J Neurol 133(Pt 1):126–138. https://doi.org/10.1093/brain/awp304

    Article  Google Scholar 

  80. Duan HQ, Wu QL, Yao X, Fan BY, Shi HY, Zhao CX, Zhang Y, Li B et al (2018) Nafamostat mesilate attenuates inflammation and apoptosis and promotes locomotor recovery after spinal cord injury. CNS Neurosci Ther 24(5):429–438. https://doi.org/10.1111/cns.12801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gao L, Xu W, Fan S, Li T, Zhao T, Ying G, Zheng J, Li J et al (2018) MANF attenuates neuronal apoptosis and promotes behavioral recovery via Akt/MDM-2/p53 pathway after traumatic spinal cord injury in rats. BioFactors. https://doi.org/10.1002/biof.1433

    CAS  Google Scholar 

  82. Wolf BB, Schuler M, Echeverri F, Green DR (1999) Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem 274(43):30651–30656

    CAS  PubMed  Google Scholar 

  83. Alawieh A, Sabra M, Sabra Z, Tomlinson S, Zaraket FA (2015) Molecular architecture of spinal cord injury protein interaction network. PLoS One 10(8):e0135024. https://doi.org/10.1371/journal.pone.0135024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Saunders NR, Noor NM, Dziegielewska KM, Wheaton BJ, Liddelow SA, Steer DL, Ek CJ, Habgood MD et al (2014) Age-dependent transcriptome and proteome following transection of neonatal spinal cord of Monodelphis domestica (South American grey short-tailed opossum). PLoS One 9(6):e99080. https://doi.org/10.1371/journal.pone.0099080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nielson JL, Paquette J, Liu AW, Guandique CF, Tovar CA, Inoue T, Irvine KA, Gensel JC et al (2015) Topological data analysis for discovery in preclinical spinal cord injury and traumatic brain injury. Nat Commun 6:8581. https://doi.org/10.1038/ncomms9581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chan SL, Mattson MP (1999) Caspase and calpain substrates: roles in synaptic plasticity and cell death. J Neurosci Res 58(1):167–190

    CAS  PubMed  Google Scholar 

  87. Malemud CJ (2006) Matrix metalloproteinases (MMPs) in health and disease: an overview. Frontiers Biosci 11:1696–1701

    CAS  Google Scholar 

  88. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, Turk D (2012) Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta 1824(1):68–88. https://doi.org/10.1016/j.bbapap.2011.10.002

    Article  CAS  PubMed  Google Scholar 

  89. Melchor JP, Strickland S (2005) Tissue plasminogen activator in central nervous system physiology and pathology. Thromb Haemost 93(4):655–660. https://doi.org/10.1160/TH04-12-0838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hegde AN, Upadhya SC (2007) The ubiquitin-proteasome pathway in health and disease of the nervous system. Trends Neurosci 30(11):587–595. https://doi.org/10.1016/j.tins.2007.08.005

    Article  CAS  PubMed  Google Scholar 

  91. Springer JE, Azbill RD, Kennedy SE, George J, Geddes JW (1997) Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment. J Neurochem 69(4):1592–1600

    CAS  PubMed  Google Scholar 

  92. Yang Z, Bramlett HM, Moghieb A, Yu D, Wang P, Lin F, Bauer C, Selig TM et al (2018) Temporal profile and severity correlation of a panel of rat spinal cord injury protein biomarkers. Mol Neurobiol 55(3):2174–2184. https://doi.org/10.1007/s12035-017-0424-7

    Article  CAS  PubMed  Google Scholar 

  93. Schumacher PA, Eubanks JH, Fehlings MG (1999) Increased calpain I-mediated proteolysis, and preferential loss of dephosphorylated NF200, following traumatic spinal cord injury. Neuroscience 91(2):733–744

    CAS  PubMed  Google Scholar 

  94. Zhu B, Li Y, Li M, Yang X, Qiu B, Gao Q, Liu J, Liu M (2013) Dynamic proteome analysis of spinal cord injury after ischemia-reperfusion in rabbits by two-dimensional difference gel electrophoresis. Spinal Cord 51(8):610–615. https://doi.org/10.1038/sc.2013.24

    Article  CAS  PubMed  Google Scholar 

  95. Banay-Schwartz M, Dahl D, Hui KS, Lajtha A (1987) The breakdown of the individual neurofilament proteins by cathepsin D. Neurochem Res 12(4):361–367

    CAS  PubMed  Google Scholar 

  96. Zhang SX, Underwood M, Landfield A, Huang FF, Gison S, Geddes JW (2000) Cytoskeletal disruption following contusion injury to the rat spinal cord. J Neuropathol Exp Neurol 59(4):287–296

    CAS  PubMed  Google Scholar 

  97. Gogel S, Lange S, Leung KY, Greene ND, Ferretti P (2010) Post-translational regulation of Crmp in developing and regenerating chick spinal cord. Development Neurobiol 70(6):456–471. https://doi.org/10.1002/dneu.20789

    Article  CAS  Google Scholar 

  98. Yokobori S, Zhang Z, Moghieb A, Mondello S, Gajavelli S, Dietrich WD, Bramlett H, Hayes RL et al (2015) Acute diagnostic biomarkers for spinal cord injury: review of the literature and preliminary research report. World Neurosurg 83(5):867–878. https://doi.org/10.1016/j.wneu.2013.03.012

    Article  PubMed  Google Scholar 

  99. Zhong ZQ, Xiang Y, Hu X, Wang YC, Zeng X, Wang XM, Xia QJ, Wang TH et al (2017) Synaptosomal-associated protein 25 may be an intervention target for improving sensory and locomotor functions after spinal cord contusion. Neural Regen Res 12(6):969–976. https://doi.org/10.4103/1673-5374.208592

    Article  PubMed  PubMed Central  Google Scholar 

  100. Gaudet AD, Popovich PG (2014) Extracellular matrix regulation of inflammation in the healthy and injured spinal cord. Exp Neurol 258:24–34

    CAS  PubMed  Google Scholar 

  101. Tauchi R, Imagama S, Ohgomori T, Natori T, Shinjo R, Ishiguro N, Kadomatsu K (2012) ADAMTS-13 is produced by glial cells and upregulated after spinal cord injury. Neurosci Lett 517(1):1–6

    CAS  PubMed  Google Scholar 

  102. Demircan K, Topcu V, Takigawa T, Akyol S, Yonezawa T, Ozturk G, Ugurcu V, Hasgul R et al (2014) ADAMTS4 and ADAMTS5 knockout mice are protected from versican but not aggrecan or brevican proteolysis during spinal cord injury. Biomed Res Int 2014:693746

    PubMed  PubMed Central  Google Scholar 

  103. Wu YP, Siao CJ, Lu W, Sung TC, Frohman MA, Milev P, Bugge TH, Degen JL et al (2000) The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate. J Cell Biol 148(6):1295–1304

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Davies JE, Tang X, Denning JW, Archibald SJ, Davies SJ (2004) Decorin suppresses neurocan, brevican, phosphacan and NG2 expression and promotes axon growth across adult rat spinal cord injuries. Eur J Neurosci 19(5):1226–1242. https://doi.org/10.1111/j.1460-9568.2004.03184.x

    Article  PubMed  Google Scholar 

  105. Lutz D, Wolters-Eisfeld G, Joshi G, Djogo N, Jakovcevski I, Schachner M, Kleene R (2012) Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1. J Biol Chem 287(21):17161–17175. https://doi.org/10.1074/jbc.M112.346759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lee JY, Choi HY, Ahn HJ, Ju BG, Yune TY (2014) Matrix metalloproteinase-3 promotes early blood-spinal cord barrier disruption and hemorrhage and impairs long-term neurological recovery after spinal cord injury. Am J Pathol 184(11):2985–3000

    CAS  PubMed  Google Scholar 

  107. Koehn LM, Noor NM, Dong Q, Er SY, Rash LD, King GF, Dziegielewska KM, Saunders NR, Habgood MD (2016) Selective inhibition of ASIC1a confers functional and morphological neuroprotection following traumatic spinal cord injury. F1000Research 5:1822. doi:https://doi.org/10.12688/f1000research.9094.2

    PubMed  PubMed Central  Google Scholar 

  108. Brocard C, Plantier V, Boulenguez P, Liabeuf S, Bouhadfane M, Viallat-Lieutaud A, Vinay L, Brocard F (2016) Cleavage of Na(+) channels by calpain increases persistent Na(+) current and promotes spasticity after spinal cord injury. Nat Med 22(4):404–411. https://doi.org/10.1038/nm.4061

    Article  CAS  PubMed  Google Scholar 

  109. Liu H, Shiryaev SA, Chernov AV, Kim Y, Shubayev I, Remacle AG, Baranovskaya S, Golubkov VS et al (2012) Immunodominant fragments of myelin basic protein initiate T cell-dependent pain. J Neuroinflammation 9:119. https://doi.org/10.1186/1742-2094-9-119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Liu D, Bao F (2015) Hydrogen peroxide administered into the rat spinal cord at the level elevated by contusion spinal cord injury oxidizes proteins, DNA and membrane phospholipids, and induces cell death: attenuation by a metalloporphyrin. Neuroscience 285:81–96. https://doi.org/10.1016/j.neuroscience.2014.10.063

    Article  CAS  PubMed  Google Scholar 

  111. Hu LY, Sun ZG, Wen YM, Cheng GZ, Wang SL, Zhao HB, Zhang XR (2010) ATP-mediated protein kinase B Akt/mammalian target of rapamycin mTOR/p70 ribosomal S6 protein p70S6 kinase signaling pathway activation promotes improvement of locomotor function after spinal cord injury in rats. Neuroscience 169(3):1046–1062. https://doi.org/10.1016/j.neuroscience.2010.05.046

    Article  CAS  PubMed  Google Scholar 

  112. Calderon-Vallejo D, Quintanar JL (2012) Gonadotropin-releasing hormone treatment improves locomotor activity, urinary function and neurofilament protein expression after spinal cord injury in ovariectomized rats. Neurosci Lett 515(2):187–190. https://doi.org/10.1016/j.neulet.2012.03.052

    Article  CAS  PubMed  Google Scholar 

  113. Burda JE, Radulovic M, Yoon H, Scarisbrick IA (2013) Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. Glia 61(9):1456–1470. https://doi.org/10.1002/glia.22534

    Article  PubMed  PubMed Central  Google Scholar 

  114. Yoon H, Radulovic M, Wu J, Blaber SI, Blaber M, Fehlings MG, Scarisbrick IA (2013) Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity. J Neurochem 127(2):283–298. https://doi.org/10.1111/jnc.12293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yoon H, Radulovic M, Walters G, Paulsen AR, Drucker K, Starski P, Wu J, Fairlie DP et al (2017) Protease activated receptor 2 controls myelin development, resiliency and repair. Glia 65(12):2070–2086. https://doi.org/10.1002/glia.23215

    Article  PubMed  PubMed Central  Google Scholar 

  116. Ma L, Yu HJ, Gan SW, Gong R, Mou KJ, Xue J, Sun SQ (2017) p53-Mediated oligodendrocyte apoptosis initiates demyelination after compressed spinal cord injury by enhancing ER-mitochondria interaction and E2F1 expression. Neurosci Lett 644:55–61. https://doi.org/10.1016/j.neulet.2017.02.038

    Article  CAS  PubMed  Google Scholar 

  117. Qiao F, Atkinson C, Song H, Pannu R, Singh I, Tomlinson S (2006) Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma. Am J Pathol 169(3):1039–1047. https://doi.org/10.2353/ajpath.2006.060248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Donnelly DJ, Longbrake EE, Shawler TM, Kigerl KA, Lai W, Tovar CA, Ransohoff RM, Popovich PG (2011) Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci 31(27):9910–9922. https://doi.org/10.1523/JNEUROSCI.2114-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lemarchant S, Pruvost M, Hebert M, Gauberti M, Hommet Y, Briens A, Maubert E, Gueye Y, Feron F, Petite D, Mersel M, do Rego JC, Vaudry H, Koistinaho J, Ali C, Agin V, Emery E, Vivien D (2014) tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury. Neurobiol Dis 66:28–42. doi:https://doi.org/10.1016/j.nbd.2014.02.005

    CAS  PubMed  Google Scholar 

  120. Bukhari N, Torres L, Robinson JK, Tsirka SE (2011) Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system. J Neurosci 31(42):14931–14943. https://doi.org/10.1523/JNEUROSCI.3339-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Takeuchi K, Yoshioka N, Higa Onaga S, Watanabe Y, Miyata S, Wada Y, Kudo C, Okada M et al (2013) Chondroitin sulphate N-acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury. Nat Commun 4:2740. https://doi.org/10.1038/ncomms3740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Tran AP, Sundar S, Yu M, Lang BT, Silver J (2018) Modulation of receptor protein tyrosine phosphatase sigma increases chondroitin sulfate proteoglycan degradation through cathepsin B secretion to enhance axon outgrowth. J Neurosci 38(23):5399–5414. https://doi.org/10.1523/JNEUROSCI.3214-17.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Devaux S, Cizkova D, Mallah K, Karnoub MA, Laouby Z, Kobeissy F, Blasko J, Nataf S et al (2017) RhoA inhibitor treatment at acute phase of spinal cord injury may induce neurite outgrowth and synaptogenesis. Molec Cell Proteom: MCP 16(8):1394–1415. https://doi.org/10.1074/mcp.M116.064881

    Article  CAS  Google Scholar 

  124. Gao K, Wang G, Wang Y, Han D, Bi J, Yuan Y, Yao T, Wan Z et al (2015) Neuroprotective effect of simvastatin via inducing the autophagy on spinal cord injury in the rat model. Biomed Res Int 2015:260161. https://doi.org/10.1155/2015/260161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Grulova I, Slovinska L, Blasko J, Devaux S, Wisztorski M, Salzet M, Fournier I, Kryukov O et al (2015) Delivery of alginate scaffold releasing two trophic factors for spinal cord injury repair. Sci Rep 5:13702. https://doi.org/10.1038/srep13702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lang BT, Cregg JM, DePaul MA, Tran AP, Xu K, Dyck SM, Madalena KM, Brown BP et al (2015) Modulation of the proteoglycan receptor PTPsigma promotes recovery after spinal cord injury. Nature 518(7539):404–408. https://doi.org/10.1038/nature13974

    Article  CAS  PubMed  Google Scholar 

  127. Menon PK, Muresanu DF, Sharma A, Mossler H, Sharma HS (2012) Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals. CNS Neurol Disord Drug Targets 11(1):40–49

    CAS  PubMed  Google Scholar 

  128. Kataria H, Lutz D, Chaudhary H, Schachner M, Loers G (2016) Small molecule agonists of cell adhesion molecule L1 mimic L1 functions in vivo. Mol Neurobiol 53(7):4461–4483. https://doi.org/10.1007/s12035-015-9352-6

    Article  CAS  PubMed  Google Scholar 

  129. Zheng B, Zhou Y, Zhang H, Yang G, Hong Z, Han D, Wang Q, He Z et al (2017) Dl-3-n-butylphthalide prevents the disruption of blood-spinal cord barrier via inhibiting endoplasmic reticulum stress following spinal cord injury. Int J Biol Sci 13(12):1520–1531. https://doi.org/10.7150/ijbs.21107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wang C, Liu C, Gao K, Zhao H, Zhou Z, Shen Z, Guo Y, Li Z et al (2016) Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. Biochem Biophys Res Commun 477(4):534–540. https://doi.org/10.1016/j.bbrc.2016.05.148

    Article  CAS  PubMed  Google Scholar 

  131. Zhang D, Tang Q, Zheng G, Wang C, Zhou Y, Wu Y, Xuan J, Tian N et al (2017) Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP-9 expression but not direct TJ proteins expression regulation. J Cell Mol Med 21(12):3322–3336. https://doi.org/10.1111/jcmm.13235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bai L, Mei X, Wang Y, Yuan Y, Bi Y, Li G, Wang H, Yan P et al (2017) The role of netrin-1 in improving functional recovery through autophagy stimulation following spinal cord injury in rats. Front Cell Neurosci 11:350. https://doi.org/10.3389/fncel.2017.00350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bai L, Mei X, Shen Z, Bi Y, Yuan Y, Guo Z, Wang H, Zhao H et al (2017) Netrin-1 Improves functional recovery through autophagy regulation by activating the AMPK/mTOR signaling pathway in rats with spinal cord injury. Sci Rep 7:42288. https://doi.org/10.1038/srep42288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wang P, Xie ZD, Xie CN, Lin CW, Wang JL, Xuan LN, Zhang CW, Wang Y et al (2018) AMP-activated protein kinase-dependent induction of autophagy by erythropoietin protects against spinal cord injury in rats. CNS Neurosci Ther 24(12):1185–1195. https://doi.org/10.1111/cns.12856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zheng B, Ye L, Zhou Y, Zhu S, Wang Q, Shi H, Chen D, Wei X et al (2016) Epidermal growth factor attenuates blood-spinal cord barrier disruption via PI3K/Akt/Rac1 pathway after acute spinal cord injury. J Cell Mol Med 20(6):1062–1075. https://doi.org/10.1111/jcmm.12761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Muresanu DF, Sharma A, Lafuente JV, Patnaik R, Tian ZR, Nyberg F, Sharma HS (2015) Nanowired delivery of growth hormone attenuates pathophysiology of spinal cord injury and enhances insulin-like growth factor-1 concentration in the plasma and the spinal cord. Mol Neurobiol 52(2):837–845. https://doi.org/10.1007/s12035-015-9298-8

    Article  CAS  PubMed  Google Scholar 

  137. Cheng Q, Sun GJ, Liu SB, Yang Q, Li XM, Li XB, Liu G, Zhao JN et al (2016) A novel translocator protein 18 kDa ligand, ZBD-2, exerts neuroprotective effects against acute spinal cord injury. Clin Exp Pharmacol Physiol 43(10):930–938. https://doi.org/10.1111/1440-1681.12606

    Article  CAS  PubMed  Google Scholar 

  138. Lee JY, Choi HY, Na WH, Ju BG, Yune TY (2015) 17beta-estradiol inhibits MMP-9 and SUR1/TrpM4 expression and activation and thereby attenuates BSCB disruption/hemorrhage after spinal cord injury in male rats. Endocrinology 156(5):1838–1850. https://doi.org/10.1210/en.2014-1832

    Article  CAS  PubMed  Google Scholar 

  139. Chakrabarti M, Banik NL, Ray SK (2014) MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons. Neuroscience 256:322–333. https://doi.org/10.1016/j.neuroscience.2013.10.027

    Article  CAS  PubMed  Google Scholar 

  140. Lee JY, Choi HY, Park CS, Ju BG, Yune TY (2018) Mithramycin A improves functional recovery by inhibiting BSCB disruption and hemorrhage after spinal cord injury. J Neurotrauma 35(3):508–520. https://doi.org/10.1089/neu.2017.5235

    Article  PubMed  Google Scholar 

  141. Lee SM, Rosen S, Weinstein P, van Rooijen N, Noble-Haeusslein LJ (2011) Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. J Neurotrauma 28(9):1893–1907. https://doi.org/10.1089/neu.2011.1860

    Article  PubMed  PubMed Central  Google Scholar 

  142. Lee JY, Kim HS, Choi HY, Oh TH, Yune TY (2012) Fluoxetine inhibits matrix metalloprotease activation and prevents disruption of blood-spinal cord barrier after spinal cord injury. Brain J Neurol 135(Pt 8):2375–2389. https://doi.org/10.1093/brain/aws171

    Article  Google Scholar 

  143. Lee JY, Choi HY, Yune TY (2016) Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury. Neuropharmacology 109:78–87. https://doi.org/10.1016/j.neuropharm.2016.05.018

    Article  CAS  PubMed  Google Scholar 

  144. Lee JY, Choi HY, Na WH, Ju BG, Yune TY (2014) Ghrelin inhibits BSCB disruption/hemorrhage by attenuating MMP-9 and SUR1/TrpM4 expression and activation after spinal cord injury. Biochimica et biophysica acta 1842 (12 Pt A):2403–2412. https://doi.org/10.1016/j.bbadis.2014.09.006

    CAS  Google Scholar 

  145. Guo J, Li Y, He Z, Zhang B, Li Y, Hu J, Han M, Xu Y et al (2014) Targeting endothelin receptors A and B attenuates the inflammatory response and improves locomotor function following spinal cord injury in mice. Int J Mol Med 34(1):74–82. https://doi.org/10.3892/ijmm.2014.1751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kumar H, Jo MJ, Choi H, Muttigi MS, Shon S, Kim BJ, Lee SH, Han IB (2018) Matrix metalloproteinase-8 Inhibition prevents disruption of blood-spinal cord barrier and attenuates inflammation in rat model of spinal cord injury. Mol Neurobiol 55(3):2577–2590. https://doi.org/10.1007/s12035-017-0509-3

    Article  CAS  Google Scholar 

  147. Oliveira KM, Lavor MS, Silva CM, Fukushima FB, Rosado IR, Silva JF, Martins BC, Guimaraes LB et al (2014) Omega-conotoxin MVIIC attenuates neuronal apoptosis in vitro and improves significant recovery after spinal cord injury in vivo in rats. Int J Clin Exp Pathol 7(7):3524–3536

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Li S, Jiang Q, Stys PK (2000) Important role of reverse Na(+)-Ca(2+) exchange in spinal cord white matter injury at physiological temperature. J Neurophysiol 84(2):1116–1119. https://doi.org/10.1152/jn.2000.84.2.1116

    Article  CAS  PubMed  Google Scholar 

  149. Colak A, Kaya M, Karaoglan A, Sagmanligil A, Akdemir O, Sahan E, Celik O (2009) Calpain inhibitor AK 295 inhibits calpain-induced apoptosis and improves neurologic function after traumatic spinal cord injury in rats. Neurocirugia 20(3):245–254

    CAS  PubMed  Google Scholar 

  150. Liabeuf S, Stuhl-Gourmand L, Gackiere F, Mancuso R, Sanchez Brualla I, Marino P, Brocard F, Vinay L (2017) Prochlorperazine Increases KCC2 Function and Reduces Spasticity after Spinal Cord Injury. J Neurotrauma 34(24):3397–3406. https://doi.org/10.1089/neu.2017.5152

    Article  PubMed  Google Scholar 

  151. Sanchez-Brualla I, Boulenguez P, Brocard C, Liabeuf S, Viallat-Lieutaud A, Navarro X, Udina E, Brocard F (2018) Activation of 5-HT2A receptors restores KCC2 function and reduces neuropathic pain after spinal cord injury. Neuroscience 387:48–57. https://doi.org/10.1016/j.neuroscience.2017.08.033

    Article  CAS  PubMed  Google Scholar 

  152. Ahmed MM, Lee H, Clark Z, Miranpuri GS, Nacht C, Patel K, Liu L, Joslin J et al (2014) Pathogenesis of spinal cord injury induced edema and neuropathic pain: expression of multiple isoforms of wnk1. Ann Neurosci 21(3):97–103. https://doi.org/10.5214/ans.0972.7531.210305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Guptarak J, Wiktorowicz JE, Sadygov RG, Zivadinovic D, Paulucci-Holthauzen AA, Vergara L, Nesic O (2014) The cancer drug tamoxifen: a potential therapeutic treatment for spinal cord injury. J Neurotrauma 31(3):268–283. https://doi.org/10.1089/neu.2013.3108

    Article  PubMed  PubMed Central  Google Scholar 

  154. Colon JM, Gonzalez PA, Cajigas A, Maldonado WI, Torrado AI, Santiago JM, Salgado IK, Miranda JD (2018) Continuous tamoxifen delivery improves locomotor recovery 6h after spinal cord injury by neuronal and glial mechanisms in male rats. Experimental neurology 299 (Pt A):109–121. https://doi.org/10.1016/j.expneurol.2017.10.006

    PubMed  Google Scholar 

  155. Xiong Y, Rabchevsky AG, Hall ED (2007) Role of peroxynitrite in secondary oxidative damage after spinal cord injury. J Neurochem 100(3):639–649

    CAS  PubMed  Google Scholar 

  156. Reeves TM, Greer JE, Vanderveer AS, Phillips LL (2010) Proteolysis of submembrane cytoskeletal proteins ankyrin-G and alphaII-spectrin following diffuse brain injury: a role in white matter vulnerability at Nodes of Ranvier. Brain Pathol 20(6):1055–1068. https://doi.org/10.1111/j.1750-3639.2010.00412.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Xiong Y, Hall ED (2009) Pharmacological evidence for a role of peroxynitrite in the pathophysiology of spinal cord injury. Exp Neurol 216(1):105–114. https://doi.org/10.1016/j.expneurol.2008.11.025

    Article  CAS  PubMed  Google Scholar 

  158. Porasuphatana S, Tsai P, Rosen GM (2003) The generation of free radicals by nitric oxide synthase. Comparat Biochem Physiol Toxicol Pharmacol: CBP 134(3):281–289

    Google Scholar 

  159. Banik NL, Matzelle DC, Gantt-Wilford G, Osborne A, Hogan EL (1997) Increased calpain content and progressive degradation of neurofilament protein in spinal cord injury. Brain Res 752(1–2):301–306

    CAS  PubMed  Google Scholar 

  160. Roerig A, Carlson R, Tipold A, Stein VM (2013) Cerebrospinal fluid tau protein as a biomarker for severity of spinal cord injury in dogs with intervertebral disc herniation. Vet J 197(2):253–258. https://doi.org/10.1016/j.tvjl.2013.02.005

    Article  CAS  PubMed  Google Scholar 

  161. Caprelli MT, Mothe AJ, Tator CH (2018) Hyperphosphorylated tau as a novel biomarker for traumatic axonal injury in the spinal cord. J Neurotrauma 35(16):1929–1941. https://doi.org/10.1089/neu.2017.5495

    Article  PubMed  Google Scholar 

  162. Radulovic M, Yoon H, Wu J, Mustafa K, Fehlings MG, Scarisbrick IA (2015) Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury. Neurobiol Dis 83:75–89. https://doi.org/10.1016/j.nbd.2015.08.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Nokkari A, Abou-El-Hassan H, Mechref Y, Mondello S, Kindy MS, Jaffa AA, Kobeissy F (2018) Implication of the kallikrein-kinin system in neurological disorders: quest for potential biomarkers and mechanisms. Prog Neurobiol 165–167:26–50. https://doi.org/10.1016/j.pneurobio.2018.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hergenroeder GW, Moore AN, Schmitt KM, Redell JB, Dash PK (2016) Identification of autoantibodies to glial fibrillary acidic protein in spinal cord injury patients. Neuroreport 27(2):90–93. https://doi.org/10.1097/WNR.0000000000000502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Song G, Cechvala C, Resnick DK, Dempsey RJ, Rao VL (2001) GeneChip analysis after acute spinal cord injury in rat. J Neurochem 79(4):804–815

    CAS  PubMed  Google Scholar 

  166. Liu MC, Akle V, Zheng W, Dave JR, Tortella FC, Hayes RL, Wang KK (2006) Comparing calpain- and caspase-3-mediated degradation patterns in traumatic brain injury by differential proteome analysis. Biochem J 394(Pt 3):715–725. https://doi.org/10.1042/BJ20050905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Afjehi-Sadat L, Brejnikow M, Kang SU, Vishwanath V, Walder N, Herkner K, Redl H, Lubec G (2010) Differential protein levels and post-translational modifications in spinal cord injury of the rat. J Proteome Res 9(3):1591–1597. https://doi.org/10.1021/pr901049a

    Article  CAS  PubMed  Google Scholar 

  168. Deng WP, Yang CC, Yang LY, Chen CW, Chen WH, Yang CB, Chen YH, Lai WF et al (2014) Extracellular matrix-regulated neural differentiation of human multipotent marrow progenitor cells enhances functional recovery after spinal cord injury. Spine J 14(10):2488–2499. https://doi.org/10.1016/j.spinee.2014.04.024

    Article  PubMed  PubMed Central  Google Scholar 

  169. Hansen CN, Fisher LC, Deibert RJ, Jakeman LB, Zhang H, Noble-Haeusslein L, White S, Basso DM (2013) Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice. J Neurosci 33(32):13101–13111. https://doi.org/10.1523/JNEUROSCI.1576-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Struve J, Maher PC, Li YQ, Kinney S, Fehlings MG, Kuntz C, Sherman LS (2005) Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation. Glia 52(1):16–24. https://doi.org/10.1002/glia.20215

    Article  PubMed  Google Scholar 

  171. Park J, Lim E, Back S, Na H, Park Y, Sun K (2010) Nerve regeneration following spinal cord injury using matrix metalloproteinase-sensitive, hyaluronic acid-based biomimetic hydrogel scaffold containing brain-derived neurotrophic factor. J Biomed Mater Res A 93(3):1091–1099

    PubMed  Google Scholar 

  172. Lubieniecka JM, Streijger F, Lee JH, Stoynov N, Liu J, Mottus R, Pfeifer T, Kwon BK et al (2011) Biomarkers for severity of spinal cord injury in the cerebrospinal fluid of rats. PLoS One 6(4):e19247. https://doi.org/10.1371/journal.pone.0019247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, Luo NL, Banine F et al (2005) Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nat Med 11(9):966–972. https://doi.org/10.1038/nm1279

    Article  CAS  PubMed  Google Scholar 

  174. Veillon L, Fakih C, Abou-El-Hassan H, Kobeissy F, Mechref Y (2018) Glycosylation changes in brain cancer. ACS Chem Neurosci 9(1):51–72. https://doi.org/10.1021/acschemneuro.7b00271

    Article  CAS  PubMed  Google Scholar 

  175. Abou-Abbass H, Abou-El-Hassan H, Bahmad H, Zibara K, Zebian A, Youssef R, Ismail J, Zhu R et al (2016) Glycosylation and other PTMs alterations in neurodegenerative diseases: current status and future role in neurotrauma. Electrophoresis 37(11):1549–1561. https://doi.org/10.1002/elps.201500585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Shields LB, Zhang YP, Burke DA, Gray R, Shields CB (2008) Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat. Surg Neurol 69(6):568–577 discussion 577

    PubMed  PubMed Central  Google Scholar 

  177. Jones LL, Margolis RU, Tuszynski MH (2003) The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol 182(2):399–411

    CAS  PubMed  Google Scholar 

  178. Nazari-Robati M, Golestani A, Asadikaram G (2016) Improvement of proteolytic and oxidative stability of chondroitinase ABC I by cosolvents. Int J Biol Macromol 91:812–817. https://doi.org/10.1016/j.ijbiomac.2016.06.030

    Article  CAS  PubMed  Google Scholar 

  179. Carwardine D, Wong LF, Fawcett JW, Muir EM, Granger N (2016) Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC. J Neurol Sci 367:311–318. https://doi.org/10.1016/j.jns.2016.06.011

    Article  CAS  PubMed  Google Scholar 

  180. Durham-Lee JC, Wu Y, Mokkapati VU, Paulucci-Holthauzen AA, Nesic O (2012) Induction of angiopoietin-2 after spinal cord injury. Neuroscience 202:454–464. https://doi.org/10.1016/j.neuroscience.2011.09.058

    Article  CAS  PubMed  Google Scholar 

  181. Wei Z, Yu D, Bi Y, Cao Y (2015) A disintegrin and metalloprotease 17 promotes microglial cell survival via epidermal growth factor receptor signalling following spinal cord injury. Mol Med Rep 12(1):63–70. https://doi.org/10.3892/mmr.2015.3395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Busch SA, Horn KP, Silver DJ, Silver J (2009) Overcoming macrophage-mediated axonal dieback following CNS injury. J Neurosci 29(32):9967–9976

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Rogers CJ, Clark PM, Tully SE, Abrol R, Garcia KC, Goddard WA 3rd, Hsieh-Wilson LC (2011) Elucidating glycosaminoglycan-protein-protein interactions using carbohydrate microarray and computational approaches. Proc Natl Acad Sci U S A 108(24):9747–9752. https://doi.org/10.1073/pnas.1102962108

    Article  PubMed  PubMed Central  Google Scholar 

  184. Sahu S, Li R, Loers G, Schachner M (2018) Knockdown of chondroitin-4-sulfotransferase-1, but not of dermatan-4-sulfotransferase-1, accelerates regeneration of zebrafish after spinal cord injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology:fj201800852RR. https://doi.org/10.1096/fj.201800852RR

    PubMed  Google Scholar 

  185. Graham ZA, Qin W, Harlow LC, Ross NH, Bauman WA, Gallagher PM, Cardozo CP (2016) Focal adhesion kinase signaling is decreased 56 days following spinal cord injury in rat gastrocnemius. Spinal Cord 54(7):502–509. https://doi.org/10.1038/sc.2015.183

    Article  CAS  PubMed  Google Scholar 

  186. Chamney C, Godar M, Garrigan E, Huey KA (2013) Effects of glutamine supplementation on muscle function and stress responses in a mouse model of spinal cord injury. Exp Physiol 98(3):796–806. https://doi.org/10.1113/expphysiol.2012.069658

    Article  CAS  PubMed  Google Scholar 

  187. Petrovic A, Kaur J, Tomljanovic I, Nistri A, Mladinic M (2018) Pharmacological induction of heat shock protein 70 by celastrol protects motoneurons from excitotoxicity in the rat spinal cord in vitro. Eur J Neurosci. https://doi.org/10.1111/ejn.14218

    PubMed  Google Scholar 

  188. Ravagnan L, Gurbuxani S, Susin SA, Maisse C, Daugas E, Zamzami N, Mak T, Jaattela M et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3(9):839–843. https://doi.org/10.1038/ncb0901-839

    Article  CAS  PubMed  Google Scholar 

  189. Sabirzhanov B, Stoica BA, Hanscom M, Piao CS, Faden AI (2012) Over-expression of HSP70 attenuates caspase-dependent and caspase-independent pathways and inhibits neuronal apoptosis. J Neurochem 123(4):542–554. https://doi.org/10.1111/j.1471-4159.2012.07927.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Yan X, Liu J, Luo Z, Ding Q, Mao X, Yan M, Yang S, Hu X et al (2010) Proteomic profiling of proteins in rat spinal cord induced by contusion injury. Neurochem Int 56(8):971–983. https://doi.org/10.1016/j.neuint.2010.04.007

    Article  CAS  PubMed  Google Scholar 

  191. Sharma HS (2010) Selected combination of neurotrophins potentiate neuroprotection and functional recovery following spinal cord injury in the rat. Acta Neurochir Suppl 106:295–300. https://doi.org/10.1007/978-3-211-98811-4_55

    Article  PubMed  Google Scholar 

  192. Vangansewinkel T, Geurts N, Quanten K, Nelissen S, Lemmens S, Geboes L, Dooley D, Vidal PM et al (2016) Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6. FASEB J 30(5):2040–2057. https://doi.org/10.1096/fj.201500114R

    Article  CAS  PubMed  Google Scholar 

  193. Nelissen S, Vangansewinkel T, Geurts N, Geboes L, Lemmens E, Vidal PM, Lemmens S, Willems L et al (2014) Mast cells protect from post-traumatic spinal cord damage in mice by degrading inflammation-associated cytokines via mouse mast cell protease 4. Neurobiol Dis 62:260–272. https://doi.org/10.1016/j.nbd.2013.09.012

    Article  CAS  PubMed  Google Scholar 

  194. Didangelos A, Puglia M, Iberl M, Sanchez-Bellot C, Roschitzki B, Bradbury EJ (2016) High-throughput proteomics reveal alarmins as amplifiers of tissue pathology and inflammation after spinal cord injury. Sci Rep 6:21607. https://doi.org/10.1038/srep21607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ahn M, Moon C, Park C, Kim J, Sim KB, Shin T (2015) Transient activation of an adaptor protein, disabled-2, in rat spinal cord injury. Acta Histochem 117(1):56–61. https://doi.org/10.1016/j.acthis.2014.11.001

    Article  CAS  PubMed  Google Scholar 

  196. da Silva BF, Meng C, Helm D, Pachl F, Schiller J, Ibrahim E, Lynne CM, Brackett NL et al (2016) Towards understanding male infertility after spinal cord injury using quantitative proteomics. Molec Cell Proteom: MCP 15(4):1424–1434. https://doi.org/10.1074/mcp.M115.052175

    Article  CAS  Google Scholar 

  197. Garraway SM, Woller SA, Huie JR, Hartman JJ, Hook MA, Miranda RC, Huang YJ, Ferguson AR et al (2014) Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis. Pain 155(11):2344–2359. https://doi.org/10.1016/j.pain.2014.08.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Xu JC, Bernreuther C, Cui YF, Jakovcevski I, Hargus G, Xiao MF, Schachner M (2011) Transplanted L1 expressing radial glia and astrocytes enhance recovery after spinal cord injury. J Neurotrauma 28(9):1921–1937. https://doi.org/10.1089/neu.2011.1783

    Article  PubMed  Google Scholar 

  199. Lutz D, Kataria H, Kleene R, Loers G, Chaudhary H, Guseva D, Wu B, Jakovcevski I et al (2016) Myelin Basic protein cleaves cell adhesion molecule L1 and improves regeneration after injury. Mol Neurobiol 53(5):3360–3376. https://doi.org/10.1007/s12035-015-9277-0

    Article  CAS  PubMed  Google Scholar 

  200. Abou-El-Hassan H, Zaraket H (2017) Viral-derived complement inhibitors: current status and potential role in immunomodulation. Exp Biol Med 242(4):397–410. https://doi.org/10.1177/1535370216675772

    Article  CAS  Google Scholar 

  201. Trivedi A, Zhang H, Ekeledo A, Lee S, Werb Z, Plant GW, Noble-Haeusslein LJ (2016) Deficiency in matrix metalloproteinase-2 results in long-term vascular instability and regression in the injured mouse spinal cord. Experimental neurology 284 (Pt A):50–62. https://doi.org/10.1016/j.expneurol.2016.07.018

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Cai XJ, Zhao JJ, Lu Y, Zhang JP, Ren BY, Cao TT, Xi GJ, Li ZW (2018) The microenvironment following oxygen glucose deprivation/re-oxygenation-induced BSCB damage in vitro. Brain Res Bull. https://doi.org/10.1016/j.brainresbull.2018.08.005

    PubMed  Google Scholar 

  203. Liu Y, Tang G, Li Y, Wang Y, Chen X, Gu X, Zhang Z, Wang Y et al (2014) Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J Neuroinflammation 11:177. https://doi.org/10.1186/s12974-014-0177-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Leonard AV, Thornton E, Vink R (2014) NK1 receptor blockade is ineffective in improving outcome following a balloon compression model of spinal cord injury. PLoS One 9(5):e98364. https://doi.org/10.1371/journal.pone.0098364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Light M, Minor KH, DeWitt P, Jasper KH, Davies SJ (2012) Multiplex array proteomics detects increased MMP-8 in CSF after spinal cord injury. J Neuroinflammation 9:122. https://doi.org/10.1186/1742-2094-9-122

    Article  PubMed  PubMed Central  Google Scholar 

  206. Dang AB, Tay BK, Kim HT, Nauth A, Alfonso-Jaume MA, Lovett DH (2008) Inhibition of MMP2/MMP9 after spinal cord trauma reduces apoptosis. Spine 33(17):E576–E579

    PubMed  Google Scholar 

  207. Levine JM, Cohen ND, Heller M, Fajt VR, Levine GJ, Kerwin SC, Trivedi AA, Fandel TM et al (2014) Efficacy of a metalloproteinase inhibitor in spinal cord injured dogs. PLoS ONE 9(5):e96408

    PubMed  PubMed Central  Google Scholar 

  208. Esposito E, Genovese T, Caminiti R, Bramanti P, Meli R, Cuzzocrea S (2008) Melatonin regulates matrix metalloproteinases after traumatic experimental spinal cord injury. J Pineal Res 45(2):149–156

    CAS  PubMed  Google Scholar 

  209. Simon CM, Sharif S, Tan RP, LaPlaca MC (2009) Spinal cord contusion causes acute plasma membrane damage. J Neurotrauma 26(4):563–574. https://doi.org/10.1089/neu.2008.0523

    Article  PubMed  PubMed Central  Google Scholar 

  210. Chua BT, Guo K, Li P (2000) Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases. J Biol Chem 275(7):5131–5135

    CAS  PubMed  Google Scholar 

  211. Liu WM, Wu JY, Li FC, Chen QX (2011) Ion channel blockers and spinal cord injury. J Neurosci Res 89(6):791–801. https://doi.org/10.1002/jnr.22602

    Article  CAS  PubMed  Google Scholar 

  212. Li S, Stys PK (2000) Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci 20(3):1190–1198

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Lenz G, Gottfried C, Luo Z, Avruch J, Rodnight R, Nie WJ, Kang Y, Neary JT (2000) P(2Y) purinoceptor subtypes recruit different mek activators in astrocytes. Br J Pharmacol 129(5):927–936. https://doi.org/10.1038/sj.bjp.0703138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Tulapurkar ME, Schafer R, Hanck T, Flores RV, Weisman GA, Gonzalez FA, Reiser G (2005) Endocytosis mechanism of P2Y2 nucleotide receptor tagged with green fluorescent protein: clathrin and actin cytoskeleton dependence. Cell Molec Life Sci: CMLS 62(12):1388–1399. https://doi.org/10.1007/s00018-005-5052-0

    Article  PubMed  Google Scholar 

  215. Rodriguez-Zayas AE, Torrado AI, Miranda JD (2010) P2Y2 receptor expression is altered in rats after spinal cord injury. Int J Develop Neurosci 28(6):413–421. https://doi.org/10.1016/j.ijdevneu.2010.07.001

    Article  CAS  Google Scholar 

  216. Yermolaieva O, Leonard AS, Schnizler MK, Abboud FM, Welsh MJ (2004) Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci U S A 101(17):6752–6757. https://doi.org/10.1073/pnas.0308636100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Hains BC, Saab CY, Waxman SG (2005) Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury. Brain J Neurol 128(Pt 10):2359–2371. https://doi.org/10.1093/brain/awh623

    Article  Google Scholar 

  218. Carmel JB, Galante A, Soteropoulos P, Tolias P, Recce M, Young W, Hart RP (2001) Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss. Physiol Genomics 7(2):201–213. https://doi.org/10.1152/physiolgenomics.00074.2001

    Article  CAS  PubMed  Google Scholar 

  219. Plantier V, Brocard F (2017) Calpain as a new therapeutic target for treating spasticity after a spinal cord injury. Med Sci 33(6–7):629–636. https://doi.org/10.1051/medsci/20173306020

    Article  Google Scholar 

  220. Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P et al (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16(3):302–307. https://doi.org/10.1038/nm.2107

    Article  CAS  PubMed  Google Scholar 

  221. Zhu YL, Xie ZL, Wu YW, Duan WR, Xie YK (2012) Early demyelination of primary A-fibers induces a rapid-onset of neuropathic pain in rat. Neuroscience 200:186–198. https://doi.org/10.1016/j.neuroscience.2011.10.037

    Article  CAS  PubMed  Google Scholar 

  222. Dubin AE, Patapoutian A (2010) Nociceptors: the sensors of the pain pathway. J Clin Invest 120(11):3760–3772. https://doi.org/10.1172/JCI42843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Hsu JY, Bourguignon LY, Adams CM, Peyrollier K, Zhang H, Fandel T, Cun CL, Werb Z et al (2008) Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. J Neurosci 28(50):13467–13477

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Tsai MC, Wei CP, Lee DY, Tseng YT, Tsai MD, Shih YL, Lee YH, Chang SF, Leu SJ (2008) Inflammatory mediators of cerebrospinal fluid from patients with spinal cord injury. Surgical Neurology 70 Suppl 1:S1:19–24; discussion S11:24

    Google Scholar 

  225. Nesic O, Guest JD, Zivadinovic D, Narayana PA, Herrera JJ, Grill RJ, Mokkapati VU, Gelman BB et al (2010) Aquaporins in spinal cord injury: the janus face of aquaporin 4. Neuroscience 168(4):1019–1035. https://doi.org/10.1016/j.neuroscience.2010.01.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Kimura A, Hsu M, Seldin M, Verkman AS, Scharfman HE, Binder DK (2010) Protective role of aquaporin-4 water channels after contusion spinal cord injury. Ann Neurol 67(6):794–801. https://doi.org/10.1002/ana.22023

    Article  PubMed  Google Scholar 

  227. Gensel JC, Donnelly DJ, Popovich PG (2011) Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages. Expert Opin Ther Targets 15(4):505–518. https://doi.org/10.1517/14728222.2011.553605

    Article  PubMed  Google Scholar 

  228. Yousefifard M, Sarveazad A, Babahajian A, Baikpour M, Shokraneh F, Vaccaro AR, Harrop JS, Fehlings MG et al (2019) Potential diagnostic and prognostic value of serum and cerebrospinal fluid biomarkers in traumatic spinal cord injury: a systematic review. J Neurochem 149(3):317–330. https://doi.org/10.1111/jnc.14637

    Article  CAS  PubMed  Google Scholar 

  229. Kwon BK, Bloom O, Wanner IB, Curt A, Schwab JM, Fawcett J, Wang KK (2019) Neurochemical biomarkers in spinal cord injury. Spinal Cord 57(10):819–831. https://doi.org/10.1038/s41393-019-0319-8

    Article  PubMed  Google Scholar 

  230. Rodrigues LF, Moura-Neto V, TCLS ES (2018) Biomarkers in spinal cord injury: from prognosis to treatment. Mol Neurobiol 55(8):6436–6448. https://doi.org/10.1007/s12035-017-0858-y

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was financially supported by a grant from the Lebanese National Council for Scientific Research (CNRS), grant award number: 103486.

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Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Hadi Abou-El-Hassan & Howard L. Weiner

  2. Division of Neurosurgery, Department of Surgery, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    Shadi Bsat & Ibrahim Omeis

  3. Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    Fares Sukhon & Edwyn Jeremy Assaf

  4. Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy

    Stefania Mondello

  5. Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

    Firas Kobeissy

  6. McKnight Brain Institute, University of Florida, Gainesville, FL, USA

    Kevin K. W. Wang

  7. Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA

    Ibrahim Omeis

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  1. Hadi Abou-El-Hassan
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HAEH wrote the paper and reviewed all cited articles. SB, FS, and EJA helped in writing the paper, drafted the tables and reviewed all cited articles. SM, FK, KWW, HW, and IO supervised and critically revised the work. All authors read and approved the final manuscript.

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Abou-El-Hassan, H., Bsat, S., Sukhon, F. et al. Protein Degradome of Spinal Cord Injury: Biomarkers and Potential Therapeutic Targets. Mol Neurobiol 57, 2702–2726 (2020). https://doi.org/10.1007/s12035-020-01916-3

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