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Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury

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Abstract

The blood-spinal cord barrier (BSCB) is a specialized protective barrier that regulates the movement of molecules between blood vessels and the spinal cord parenchyma. Analogous to the blood-brain barrier (BBB), the BSCB plays a crucial role in maintaining the homeostasis and internal environmental stability of the central nervous system (CNS). After spinal cord injury (SCI), BSCB disruption leads to inflammatory cell invasion such as neutrophils and macrophages, contributing to permanent neurological disability. In this review, we focus on the major proteins mediating the BSCB disruption or BSCB repair after SCI. This review is composed of three parts. Section 1. SCI and the BSCB of the review describes critical events involved in the pathophysiology of SCI and their correlation with BSCB integrity/disruption. Section 2. Major proteins involved in BSCB disruption in SCI focuses on the actions of matrix metalloproteinases (MMPs), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), angiopoietins (Angs), bradykinin, nitric oxide (NO), and endothelins (ETs) in BSCB disruption and repair. Section 3. Therapeutic approaches discusses the major therapeutic compounds utilized to date for the prevention of BSCB disruption in animal model of SCI through modulation of several proteins.

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References

  1. Bartanusz V, Jezova D, Alajajian B, Digicaylioglu M (2011) The blood-spinal cord barrier: morphology and clinical implications. Ann Neurol 70(2):194–206. doi:10.1002/ana.22421

    Article  PubMed  Google Scholar 

  2. Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84(3):869–901. doi:10.1152/physrev.00035.2003

    Article  CAS  PubMed  Google Scholar 

  3. Begley DJ, Brightman MW (2003) Structural and functional aspects of the blood-brain barrier. Prog Drug Res 61:39–78

    CAS  PubMed  Google Scholar 

  4. 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. doi:10.1093/brain/aws171

    Article  Google Scholar 

  5. Palmer AM (2013) Multiple sclerosis and the blood-central nervous system barrier. Cardiovasc Psychiatry Neurol 2013:530356. doi:10.1155/2013/530356

    Article  PubMed Central  PubMed  Google Scholar 

  6. Vincent T, Saikali P, Cayrol R, Roth AD, Bar-Or A, Prat A, Antel JP (2008) Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment. J Immunol 181(8):5730–5737

    Article  CAS  PubMed  Google Scholar 

  7. Garbuzova-Davis S, Saporta S, Sanberg PR (2008) Implications of blood-brain barrier disruption in ALS. Amyotroph Lateral Scler 9(6):375–376

    Article  PubMed  Google Scholar 

  8. Hemley SJ, Tu J, Stoodley MA (2009) Role of the blood-spinal cord barrier in posttraumatic syringomyelia. J Neurosurg Spine 11(6):696–704. doi:10.3171/2009.6.SPINE08564

    Article  PubMed  Google Scholar 

  9. Cahill LS, Laliberté CL, Liu XJ, Bishop J, Nieman BJ, Mogil JS, Sorge RE, Jones CD et al (2014) Quantifying blood-spinal cord barrier permeability after peripheral nerve injury in the living mouse. Mol Pain 10(1):60

    PubMed Central  PubMed  Google Scholar 

  10. Li XQ, Lv HW, Wang ZL, Tan WF, Fang B, Ma H (2015) MiR-27a ameliorates inflammatory damage to the blood-spinal cord barrier after spinal cord ischemia: reperfusion injury in rats by downregulating TICAM-2 of the TLR4 signaling pathway. J Neuroinflammation 12(1):25. doi:10.1186/s12974-015-0246-3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Maikos JT, Shreiber DI (2007) Immediate damage to the blood-spinal cord barrier due to mechanical trauma. J Neurotrauma 24(3):492–507. doi:10.1089/neu.2006.0149

    Article  PubMed  Google Scholar 

  12. Noble LJ, Wrathall JR (1989) Distribution and time course of protein extravasation in the rat spinal cord after contusive injury. Brain Res 482(1):57–66

    Article  CAS  PubMed  Google Scholar 

  13. Whetstone WD, Hsu JY, Eisenberg M, Werb Z, Noble-Haeusslein LJ (2003) Blood-spinal cord barrier after spinal cord injury: relation to revascularization and wound healing. J Neurosci Res 74(2):227–239. doi:10.1002/jnr.10759

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Rossignol S, Schwab M, Schwartz M, Fehlings MG (2007) Spinal cord injury: time to move? J Neurosci Off J Soc Neurosci 27(44):11782–11792. doi:10.1523/JNEUROSCI.3444-07.2007

    Article  CAS  Google Scholar 

  15. Acarin L, Gonzalez B, Castellano B (2000) Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. Eur J Neurosci 12(10):3505–3520

    Article  CAS  PubMed  Google Scholar 

  16. Bartholdi D, Schwab ME (1997) Expression of pro-inflammatory cytokine and chemokine mRNA upon experimental spinal cord injury in mouse: an in situ hybridization study. Eur J Neurosci 9(7):1422–1438

    Article  CAS  PubMed  Google Scholar 

  17. Hayashi M, Ueyama T, Nemoto K, Tamaki T, Senba E (2000) Sequential mRNA expression for immediate early genes, cytokines, and neurotrophins in spinal cord injury. J Neurotrauma 17(3):203–218

    Article  CAS  PubMed  Google Scholar 

  18. Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS (2001) Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24(5):254–264

    Article  CAS  PubMed  Google Scholar 

  19. Tator CH (1996) Experimental and clinical studies of the pathophysiology and management of acute spinal cord injury. J Spinal Cord Med 19(4):206–214

    Article  CAS  PubMed  Google Scholar 

  20. Grossman SD, Rosenberg LJ, Wrathall JR (2001) Temporal-spatial pattern of acute neuronal and glial loss after spinal cord contusion. Exp Neurol 168(2):273–282. doi:10.1006/exnr.2001.7628

    Article  CAS  PubMed  Google Scholar 

  21. Beattie MS, Hermann GE, Rogers RC, Bresnahan JC (2002) Cell death in models of spinal cord injury. Prog Brain Res 137:37–47

    Article  PubMed  Google Scholar 

  22. Degeneration and regeneration of the nervous system (1928) Oxford UP

  23. Clemente CD, Windle WF (1954) Regeneration of severed nerve fibers in the spinal cord of the adult cat. J Comp Neurol 101(3):691–731

    Article  CAS  PubMed  Google Scholar 

  24. Liuzzi FJ, Lasek RJ (1987) Astrocytes block axonal regeneration in mammals by activating the physiological stop pathway. Science 237(4815):642–645

    Article  CAS  PubMed  Google Scholar 

  25. Rudge JS, Silver J (1990) Inhibition of neurite outgrowth on astroglial scars in vitro. J Neurosci Off J Soc Neurosci 10(11):3594–3603

    CAS  Google Scholar 

  26. Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185. doi:10.1124/pr.57.2.4

    Article  CAS  PubMed  Google Scholar 

  27. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201. doi:10.1016/j.neuron.2008.01.003

    Article  CAS  PubMed  Google Scholar 

  28. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7(1):41–53. doi:10.1038/nrn1824

    Article  CAS  PubMed  Google Scholar 

  29. Popovich PG, Horner PJ, Mullin BB, Stokes BT (1996) A quantitative spatial analysis of the blood-spinal cord barrier. I. Permeability changes after experimental spinal contusion injury. Exp Neurol 142(2):258–275. doi:10.1006/exnr.1996.0196

    Article  CAS  PubMed  Google Scholar 

  30. Cohen DM, Patel CB, Ahobila-Vajjula P, Sundberg LM, Chacko T, Liu SJ, Narayana PA (2009) Blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced MRI. NMR Biomed 22(3):332–341. doi:10.1002/nbm.1343

    Article  PubMed Central  PubMed  Google Scholar 

  31. Runge VM, Wells JW, Baldwin SA, Scheff SW, Blades DA (1997) Evaluation of the temporal evolution of acute spinal cord injury. Investig Radiol 32(2):105–110

    Article  CAS  Google Scholar 

  32. Figley SA, Khosravi R, Legasto JM, Tseng YF, Fehlings MG (2014) Characterization of vascular disruption and blood-spinal cord barrier permeability following traumatic spinal cord injury. J Neurotrauma 31(6):541–552. doi:10.1089/neu.2013.3034

    Article  PubMed Central  PubMed  Google Scholar 

  33. Ankeny DP, Popovich PG (2009) Mechanisms and implications of adaptive immune responses after traumatic spinal cord injury. Neuroscience 158(3):1112–1121. doi:10.1016/j.neuroscience.2008.07.001

    Article  CAS  PubMed  Google Scholar 

  34. Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5(2):146–156. doi:10.1038/nrn1326

    Article  CAS  PubMed  Google Scholar 

  35. Leal-Filho MB (2011) Spinal cord injury: from inflammation to glial scar. Surg Neurol Int 2:112. doi:10.4103/2152-7806.83732

    Article  PubMed Central  PubMed  Google Scholar 

  36. Aube B, Levesque SA, Pare A, Chamma E, Kebir H, Gorina R, Lecuyer MA, Alvarez JI et al (2014) Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases. J Immunol 193(5):2438–2454. doi:10.4049/jimmunol.1400401

    Article  CAS  PubMed  Google Scholar 

  37. Noble LJ, Wrathall JR (1988) Blood-spinal cord barrier disruption proximal to a spinal cord transection in the rat: time course and pathways associated with protein leakage. Exp Neurol 99(3):567–578

    Article  CAS  PubMed  Google Scholar 

  38. 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. doi:10.3171/jns.1991.75.1.0015

    Article  CAS  PubMed  Google Scholar 

  39. Noble LJ, Mautes AE, Hall JJ (1996) Characterization of the microvascular glycocalyx in normal and injured spinal cord in the rat. J Comp Neurol 376(4):542–556. doi:10.1002/(SICI)1096-9861(19961223)376:4<542::AID-CNE4>3.0.CO;2-1

    Article  CAS  PubMed  Google Scholar 

  40. 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 Off J Soc Neurosci 22(17):7526–7535

    CAS  Google Scholar 

  41. Stirling DP, Yong VW (2008) Dynamics of the inflammatory response after murine spinal cord injury revealed by flow cytometry. J Neurosci Res 86(9):1944–1958. doi:10.1002/jnr.21659

    Article  CAS  PubMed  Google Scholar 

  42. Simard JM, Woo SK, Norenberg MD, Tosun C, Chen Z, Ivanova S, Tsymbalyuk O, Bryan J et al (2010) Brief suppression of Abcc8 prevents autodestruction of spinal cord after trauma. Sci Transl Med 2(28):28ra29. doi:10.1126/scitranslmed.3000522

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong Z et al (2014) Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci U S A 111(11):E1035–E1042. doi:10.1073/pnas.1401595111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Sharma HS (2011) Early microvascular reactions and blood-spinal cord barrier disruption are instrumental in pathophysiology of spinal cord injury and repair: novel therapeutic strategies including nanowired drug delivery to enhance neuroprotection. J Neural Transm 118(1):155–176. doi:10.1007/s00702-010-0514-4

    Article  CAS  PubMed  Google Scholar 

  45. Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Werb Z (1997) ECM and cell surface proteolysis: regulating cellular ecology. Cell 91(4):439–442

    Article  CAS  PubMed  Google Scholar 

  47. Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29(10):2189–2195

    Article  CAS  PubMed  Google Scholar 

  48. Liu W, Hendren J, Qin XJ, Shen J, Liu KJ (2009) Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem 108(3):811–820. doi:10.1111/j.1471-4159.2008.05821.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Gurney KJ, Estrada EY, Rosenberg GA (2006) Blood-brain barrier disruption by stromelysin-1 facilitates neutrophil infiltration in neuroinflammation. Neurobiol Dis 23(1):87–96. doi:10.1016/j.nbd.2006.02.006

    Article  CAS  PubMed  Google Scholar 

  50. Mautes AE, Weinzierl MR, Donovan F, Noble LJ (2000) Vascular events after spinal cord injury: contribution to secondary pathogenesis. Phys Ther 80(7):673–687

    CAS  PubMed  Google Scholar 

  51. Carlson SL, Parrish ME, Springer JE, Doty K, Dossett L (1998) Acute inflammatory response in spinal cord following impact injury. Exp Neurol 151(1):77–88. doi:10.1006/exnr.1998.6785

    Article  CAS  PubMed  Google Scholar 

  52. Caron A, Desrosiers RR, Beliveau R (2005) Ischemia injury alters endothelial cell properties of kidney cortex: stimulation of MMP-9. Exp Cell Res 310(1):105–116. doi:10.1016/j.yexcr.2005.07.004

    Article  CAS  PubMed  Google Scholar 

  53. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27(4):697–709. doi:10.1038/sj.jcbfm.9600375

    Article  CAS  PubMed  Google Scholar 

  54. Hsu JY, McKeon R, Goussev S, Werb Z, Lee JU, Trivedi A, Noble-Haeusslein LJ (2006) Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J Neurosci Off J Soc Neurosci 26(39):9841–9850. doi:10.1523/JNEUROSCI.1993-06.2006

    Article  CAS  Google Scholar 

  55. 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 Off J Soc Neurosci 23(31):10107–10115

    CAS  Google Scholar 

  56. Zuo J, Ferguson TA, Hernandez YJ, Stetler-Stevenson WG, Muir D (1998) Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan. J Neurosci Off J Soc Neurosci 18(14):5203–5211

    CAS  Google Scholar 

  57. 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. doi:10.1016/j.ajpath.2014.07.016

    Article  CAS  PubMed  Google Scholar 

  58. 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. doi:10.1089/neu.2007.0438

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  60. Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD (1996) Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc Natl Acad Sci U S A 93(9):3942–3946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Davies AL, Hayes KC, Dekaban GA (2007) Clinical correlates of elevated serum concentrations of cytokines and autoantibodies in patients with spinal cord injury. Arch Phys Med Rehabil 88(11):1384–1393. doi:10.1016/j.apmr.2007.08.004

    Article  PubMed  Google Scholar 

  62. Leskovar A, Moriarty LJ, Turek JJ, Schoenlein IA, Borgens RB (2000) The macrophage in acute neural injury: changes in cell numbers over time and levels of cytokine production in mammalian central and peripheral nervous systems. J Exp Biol 203(Pt 12):1783–1795

    CAS  PubMed  Google Scholar 

  63. Pan W, Kastin AJ (2001) Increase in TNFalpha transport after SCI is specific for time, region, and type of lesion. Exp Neurol 170(2):357–363. doi:10.1006/exnr.2001.7702

    Article  CAS  PubMed  Google Scholar 

  64. Lee YB, Yune TY, Baik SY, Shin YH, Du S, Rhim H, Lee EB, Kim YC et al (2000) Role of tumor necrosis factor-alpha in neuronal and glial apoptosis after spinal cord injury. Exp Neurol 166(1):190–195. doi:10.1006/exnr.2000.7494

    Article  CAS  PubMed  Google Scholar 

  65. Pan W, Banks WA, Kastin AJ (1997) Blood-brain barrier permeability to ebiratide and TNF in acute spinal cord injury. Exp Neurol 146(2):367–373. doi:10.1006/exnr.1997.6533

    Article  CAS  PubMed  Google Scholar 

  66. Bethea JR, Nagashima H, Acosta MC, Briceno C, Gomez F, Marcillo AE, Loor K, Green J et al (1999) Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 16(10):851–863

    Article  CAS  PubMed  Google Scholar 

  67. Lotan M, Solomon A, Ben-Bassat S, Schwartz M (1994) Cytokines modulate the inflammatory response and change permissiveness to neuronal adhesion in injured mammalian central nervous system. Exp Neurol 126(2):284–290. doi:10.1006/exnr.1994.1066

    Article  CAS  PubMed  Google Scholar 

  68. Franzen R, Schoenen J, Leprince P, Joosten E, Moonen G, Martin D (1998) Effects of macrophage transplantation in the injured adult rat spinal cord: a combined immunocytochemical and biochemical study. J Neurosci Res 51(3):316–327

    Article  CAS  PubMed  Google Scholar 

  69. Li GL, Brodin G, Farooque M, Funa K, Holtz A, Wang WL, Olsson Y (1996) Apoptosis and expression of Bcl-2 after compression trauma to rat spinal cord. J Neuropathol Exp Neurol 55(3):280–289

    Article  CAS  PubMed  Google Scholar 

  70. Probert L, Selmaj K (1997) TNF and related molecules: trends in neuroscience and clinical applications. J Neuroimmunol 72(2):113–117

    Article  CAS  PubMed  Google Scholar 

  71. Probert L, Akassoglou K, Kassiotis G, Pasparakis M, Alexopoulou L, Kollias G (1997) TNF-alpha transgenic and knockout models of CNS inflammation and degeneration. J Neuroimmunol 72(2):137–141

    Article  CAS  PubMed  Google Scholar 

  72. Trickler WJ, Mayhan WG, Miller DW (2005) Brain microvessel endothelial cell responses to tumor necrosis factor-alpha involve a nuclear factor kappa B (NF-kappaB) signal transduction pathway. Brain Res 1048(1-2):24–31. doi:10.1016/j.brainres.2005.04.028

    Article  CAS  PubMed  Google Scholar 

  73. He F, Peng J, Deng XL, Yang LF, Camara AD, Omran A, Wang GL, Wu LW et al (2012) Mechanisms of tumor necrosis factor-alpha-induced leaks in intestine epithelial barrier. Cytokine 59(2):264–272. doi:10.1016/j.cyto.2012.04.008

    Article  CAS  PubMed  Google Scholar 

  74. Camussi G, Turello E, Bussolino F, Baglioni C (1991) Tumor necrosis factor alters cytoskeletal organization and barrier function of endothelial cells. Int Arch Allergy Appl Immunol 96(1):84–91

    Article  CAS  PubMed  Google Scholar 

  75. Kim KS, Wass CA, Cross AS, Opal SM (1992) Modulation of blood-brain barrier permeability by tumor necrosis factor and antibody to tumor necrosis factor in the rat. Lymphokine Cytokine Res 11(6):293–298

    CAS  PubMed  Google Scholar 

  76. Duchini A, Govindarajan S, Santucci M, Zampi G, Hofman FM (1996) Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 44(8):474–482

    CAS  PubMed  Google Scholar 

  77. Pan W, Kastin AJ (2002) TNFalpha transport across the blood-brain barrier is abolished in receptor knockout mice. Exp Neurol 174(2):193–200. doi:10.1006/exnr.2002.7871

    Article  CAS  PubMed  Google Scholar 

  78. Pan W, Csernus B, Kastin AJ (2003) Upregulation of p55 and p75 receptors mediating TNF-alpha transport across the injured blood-spinal cord barrier. J Mol Neurosci: MN 21(2):173–184. doi:10.1385/JMN:21:2:173

    Article  CAS  PubMed  Google Scholar 

  79. Pan W, Kastin AJ, Bell RL, Olson RD (1999) Upregulation of tumor necrosis factor alpha transport across the blood-brain barrier after acute compressive spinal cord injury. J Neurosci Off J Soc Neurosci 19(9):3649–3655

    CAS  Google Scholar 

  80. Kim GM, Xu J, Song SK, Yan P, Ku G, Xu XM, Hsu CY (2001) Tumor necrosis factor receptor deletion reduces nuclear factor-kappaB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J Neurosci Off J Soc Neurosci 21(17):6617–6625

    CAS  Google Scholar 

  81. Kumar H, Lim HW, More SV, Kim BW, Koppula S, Kim IS, Choi DK (2012) The role of free radicals in the aging brain and Parkinson’s disease: convergence and parallelism. Int J Mol Sci 13(8):10478–10504. doi:10.3390/ijms130810478

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. McCoubrey WK Jr, Maines MD (1994) The structure, organization and differential expression of the gene encoding rat heme oxygenase-2. Gene 139(2):155–161

    Article  CAS  PubMed  Google Scholar 

  83. McCoubrey WK Jr, Huang TJ, Maines MD (1997) Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem/FEBS 247(2):725–732

    Article  CAS  Google Scholar 

  84. McCoubrey WK Jr, Huang TJ, Maines MD (1997) Heme oxygenase-2 is a hemoprotein and binds heme through heme regulatory motifs that are not involved in heme catalysis. J Biol Chem 272(19):12568–12574

    Article  CAS  PubMed  Google Scholar 

  85. Panahian N, Maines MD (2001) Site of injury-directed induction of heme oxygenase-1 and -2 in experimental spinal cord injury: differential functions in neuronal defense mechanisms? J Neurochem 76(2):539–554

    Article  CAS  PubMed  Google Scholar 

  86. Mautes AE, Bergeron M, Sharp FR, Panter SS, Weinzierl M, Guenther K, Noble LJ (2000) Sustained induction of heme oxygenase-1 in the traumatized spinal cord. Exp Neurol 166(2):254–265. doi:10.1006/exnr.2000.7520

    Article  CAS  PubMed  Google Scholar 

  87. Liu Y, Tachibana T, Dai Y, Kondo E, Fukuoka T, Yamanaka H, Noguchi K (2002) Heme oxygenase-1 expression after spinal cord injury: the induction in activated neutrophils. J Neurotrauma 19(4):479–490. doi:10.1089/08977150252932424

    Article  PubMed  Google Scholar 

  88. Mautes AE, Kim DH, Sharp FR, Panter S, Sato M, Maida N, Bergeron M, Guenther K et al (1998) Induction of heme oxygenase-1 (HO-1) in the contused spinal cord of the rat. Brain Res 795(1-2):17–24

    Article  CAS  PubMed  Google Scholar 

  89. Lin Y, Vreman HJ, Wong RJ, Tjoa T, Yamauchi T, Noble-Haeusslein LJ (2007) Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord. J Cereb Blood Flow Metab 27(5):1010–1021. doi:10.1038/sj.jcbfm.9600412

    Article  CAS  PubMed  Google Scholar 

  90. Yamauchi T, Lin Y, Sharp FR, Noble-Haeusslein LJ (2004) Hemin induces heme oxygenase-1 in spinal cord vasculature and attenuates barrier disruption and neutrophil infiltration in the injured murine spinal cord. J Neurotrauma 21(8):1017–1030. doi:10.1089/0897715041651042

    Article  PubMed  Google Scholar 

  91. Kapturczak MH, Wasserfall C, Brusko T, Campbell-Thompson M, Ellis TM, Atkinson MA, Agarwal A (2004) Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am J Pathol 165(3):1045–1053. doi:10.1016/S0002-9440(10)63365-2

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y et al (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103(1):129–135. doi:10.1172/JCI4165

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Wagener FA, da Silva JL, Farley T, de Witte T, Kappas A, Abraham NG (1999) Differential effects of heme oxygenase isoforms on heme mediation of endothelial intracellular adhesion molecule 1 expression. J Pharmacol Exp Ther 291(1):416–423

    CAS  PubMed  Google Scholar 

  94. Justicia C, Panes J, Sole S, Cervera A, Deulofeu R, Chamorro A, Planas AM (2003) Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab 23(12):1430–1440. doi:10.1097/01.WCB.0000090680.07515.C8

    Article  CAS  PubMed  Google Scholar 

  95. Lee TS, Chau LY (2002) Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 8(3):240–246. doi:10.1038/nm0302-240

    Article  CAS  PubMed  Google Scholar 

  96. Mautes AE, Noble LJ (2000) Co-induction of HSP70 and heme oxygenase-1 in macrophages and glia after spinal cord contusion in the rat. Brain Res 883(2):233–237

    Article  CAS  PubMed  Google Scholar 

  97. Wang N, Wang G, Hao J, Ma J, Wang Y, Jiang X, Jiang H (2012) Curcumin ameliorates hydrogen peroxide-induced epithelial barrier disruption by upregulating heme oxygenase-1 expression in human intestinal epithelial cells. Dig Dis Sci 57(7):1792–1801. doi:10.1007/s10620-012-2094-7

    Article  CAS  PubMed  Google Scholar 

  98. Thomas M, Augustin HG (2009) The role of the Angiopoietins in vascular morphogenesis. Angiogenesis 12(2):125–137. doi:10.1007/s10456-009-9147-3

    Article  CAS  PubMed  Google Scholar 

  99. Hansen TM, Moss AJ, Brindle NP (2008) Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr Neurovasc Res 5(4):236–245

    Article  CAS  PubMed  Google Scholar 

  100. Zacharek A, Chen J, Cui X, Li A, Li Y, Roberts C, Feng Y, Gao Q et al (2007) Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke. J Cereb Blood Flow Metab 27(10):1684–1691. doi:10.1038/sj.jcbfm.9600475

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Kim H, Lee JM, Park JS, Jo SA, Kim YO, Kim CW, Jo I (2008) Dexamethasone coordinately regulates angiopoietin-1 and VEGF: a mechanism of glucocorticoid-induced stabilization of blood-brain barrier. Biochem Biophys Res Commun 372(1):243–248. doi:10.1016/j.bbrc.2008.05.025

    Article  PubMed  CAS  Google Scholar 

  102. Han S, Arnold SA, Sithu SD, Mahoney ET, Geralds JT, Tran P, Benton RL, Maddie MA et al (2010) Rescuing vasculature with intravenous angiopoietin-1 and alpha v beta 3 integrin peptide is protective after spinal cord injury. Brain J Neurol 133(Pt 4):1026–1042. doi:10.1093/brain/awq034

    Article  Google Scholar 

  103. Ritz MF, Graumann U, Gutierrez B, Hausmann O (2010) Traumatic spinal cord injury alters angiogenic factors and TGF-beta1 that may affect vascular recovery. Curr Neurovasc Res 7(4):301–310

    Article  CAS  PubMed  Google Scholar 

  104. Herrera JJ, Sundberg LM, Zentilin L, Giacca M, Narayana PA (2010) Sustained expression of vascular endothelial growth factor and angiopoietin-1 improves blood-spinal cord barrier integrity and functional recovery after spinal cord injury. J Neurotrauma 27(11):2067–2076. doi:10.1089/neu.2010.1403

    Article  PubMed Central  PubMed  Google Scholar 

  105. Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG et al (1999) Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S A 96(5):1904–1909

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. 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. doi:10.1016/j.neuroscience.2011.09.058

    Article  CAS  PubMed  Google Scholar 

  107. Gamble JR, Drew J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos G et al (2000) Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res 87(7):603–607

    Article  CAS  PubMed  Google Scholar 

  108. Nourhaghighi N, Teichert-Kuliszewska K, Davis J, Stewart DJ, Nag S (2003) Altered expression of angiopoietins during blood-brain barrier breakdown and angiogenesis. Lab Invest 83(8):1211–1222

    Article  CAS  PubMed  Google Scholar 

  109. Valable S, Montaner J, Bellail A, Berezowski V, Brillault J, Cecchelli R, Divoux D, Mackenzie ET et al (2005) VEGF-induced BBB permeability is associated with an MMP-9 activity increase in cerebral ischemia: both effects decreased by Ang-1. J Cereb Blood Flow Metab 25(11):1491–1504. doi:10.1038/sj.jcbfm.9600148

    Article  CAS  PubMed  Google Scholar 

  110. Nambu H, Nambu R, Oshima Y, Hackett SF, Okoye G, Wiegand S, Yancopoulos G, Zack DJ et al (2004) Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood-retinal barrier. Gene Ther 11(10):865–873. doi:10.1038/sj.gt.3302230

    Article  CAS  PubMed  Google Scholar 

  111. Stewart JM, Gera L, Chan DC, Whalley ET, Hanson WL, Zuzack JS (1997) Potent, long-acting bradykinin antagonists for a wide range of applications. Can J Physiol Pharmacol 75(6):719–724

    Article  CAS  PubMed  Google Scholar 

  112. Marmarou A, Nichols J, Burgess J, Newell D, Troha J, Burnham D, Pitts L (1999) Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. American Brain Inj Consortium Study Group J Neurotrauma 16(6):431–444

    CAS  Google Scholar 

  113. Narotam PK, Rodell TC, Nadvi SS, Bhoola KD, Troha JM, Parbhoosingh R, van Dellen JR (1998) Traumatic brain contusions: a clinical role for the kinin antagonist CP-0127. Acta Neurochir 140(8):793–802, discussion 802-793

    Article  CAS  PubMed  Google Scholar 

  114. Zausinger S, Lumenta DB, Pruneau D, Schmid-Elsaesser R, Plesnila N, Baethmann A (2002) Effects of LF 16-0687 Ms, a bradykinin B(2) receptor antagonist, on brain edema formation and tissue damage in a rat model of temporary focal cerebral ischemia. Brain Res 950(1-2):268–278

    Article  CAS  PubMed  Google Scholar 

  115. Sharma HS (2000) A bradykinin BK2 receptor antagonist HOE-140 attenuates blood-spinal cord barrier permeability following a focal trauma to the rat spinal cord. In: Brain Edema XI. Springer, Berlin, pp 159–163

    Chapter  Google Scholar 

  116. Pan W, Kastin AJ, Gera L, Stewart JM (2001) Bradykinin antagonist decreases early disruption of the blood-spinal cord barrier after spinal cord injury in mice. Neurosci Lett 307(1):25–28

    Article  CAS  PubMed  Google Scholar 

  117. Yan-Feng W, Gang L, Yan-Ting G (2008) Bradykinin preconditioning induces protective effects on the spinal cord ischemic injury of rats. Neurosci Lett 433(2):114–118. doi:10.1016/j.neulet.2008.01.010

    Article  PubMed  CAS  Google Scholar 

  118. Mechirova E, Danielisova V, Domorakova I, Dankova M, Stebnicky M, Mickova H, Burda J (2014) Bradykinin preconditioning affects the number of degenerated neurons and the level of antioxidant enzymes in spinal cord ischemia in rabbits. Acta Histochem 116(1):252–257. doi:10.1016/j.acthis.2013.07.010

    Article  CAS  PubMed  Google Scholar 

  119. Laroux FS, Pavlick KP, Hines IN, Kawachi S, Harada H, Bharwani S, Hoffman JM, Grisham MB (2001) Role of nitric oxide in inflammation. Acta Physiol Scand 173(1):113–118. doi:10.1046/j.1365-201X.2001.00891.x

    Article  CAS  PubMed  Google Scholar 

  120. Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biochem J 298(Pt 2):249–258

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Koppenol WH, Traynham JG (1996) Say NO to nitric oxide: nomenclature for nitrogen- and oxygen-containing compounds. Methods Enzymol 268:3–7

    Article  CAS  PubMed  Google Scholar 

  122. Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63:175–195. doi:10.1146/annurev.bi.63.070194.001135

    Article  CAS  PubMed  Google Scholar 

  123. Xiong Y, Rabchevsky AG, Hall ED (2007) Role of peroxynitrite in secondary oxidative damage after spinal cord injury. J Neurochem 100(3):639–649. doi:10.1111/j.1471-4159.2006.04312.x

    Article  CAS  PubMed  Google Scholar 

  124. Carrico KM, Vaishnav R, Hall ED (2009) Temporal and spatial dynamics of peroxynitrite-induced oxidative damage after spinal cord contusion injury. J Neurotrauma 26(8):1369–1378. doi:10.1089/neu.2008-0870

    Article  PubMed Central  PubMed  Google Scholar 

  125. Marsala J, Kluchova D, Marsala M (1997) Spinal cord gray matter layers rich in NADPH diaphorase-positive neurons are refractory to ischemia-reperfusion-induced injury: a histochemical and silver impregnation study in rabbit. Exp Neurol 145(1):165–179. doi:10.1006/exnr.1997.6455

    Article  CAS  PubMed  Google Scholar 

  126. Hama AT, Sagen J (1994) Induction of spinal NADPH-diaphorase by nerve injury is attenuated by adrenal medullary transplants. Brain Res 640(1-2):345–351

    Article  CAS  PubMed  Google Scholar 

  127. Vincent SR (1994) Nitric oxide: a radical neurotransmitter in the central nervous system. Prog Neurobiol 42(1):129–160

    Article  CAS  PubMed  Google Scholar 

  128. Liu D, Ling X, Wen J, Liu J (2000) The role of reactive nitrogen species in secondary spinal cord injury: formation of nitric oxide, peroxynitrite, and nitrated protein. J Neurochem 75(5):2144–2154

    Article  CAS  PubMed  Google Scholar 

  129. Hamada Y, Ikata T, Katoh S, Tsuchiya K, Niwa M, Tsutsumishita Y, Fukuzawa K (1996) Roles of nitric oxide in compression injury of rat spinal cord. Free Radic Biol Med 20(1):1–9

    Article  CAS  PubMed  Google Scholar 

  130. Nakahara S, Yone K, Setoguchi T, Yamaura I, Arishima Y, Yoshino S, Komiya S (2002) Changes in nitric oxide and expression of nitric oxide synthase in spinal cord after acute traumatic injury in rats. J Neurotrauma 19(11):1467–1474. doi:10.1089/089771502320914697

    Article  PubMed  Google Scholar 

  131. Sharma HS, Nyberg F, Westman J, Alm P, Gordh T, Lindholm D (1998) Brain derived neurotrophic factor and insulin like growth factor-1 attenuate upregulation of nitric oxide synthase and cell injury following trauma to the spinal cord. An immunohistochemical study in the rat. Amino Acids 14(1-3):121–129

    Article  PubMed  Google Scholar 

  132. Sharma HS (2010) A combination of tumor necrosis factor-alpha and neuronal nitric oxide synthase antibodies applied topically over the traumatized spinal cord enhances neuroprotection and functional recovery in the rat. Ann N Y Acad Sci 1199:175–185. doi:10.1111/j.1749-6632.2009.05327.x

    Article  CAS  PubMed  Google Scholar 

  133. Pearse DD, Chatzipanteli K, Marcillo AE, Bunge MB, Dietrich WD (2003) Comparison of iNOS inhibition by antisense and pharmacological inhibitors after spinal cord injury. J Neuropathol Exp Neurol 62(11):1096–1107

    Article  CAS  PubMed  Google Scholar 

  134. Maggio DM, Chatzipanteli K, Masters N, Patel SP, Dietrich WD, Pearse DD (2012) Acute molecular perturbation of inducible nitric oxide synthase with an antisense approach enhances neuronal preservation and functional recovery after contusive spinal cord injury. J Neurotrauma 29(12):2244–2249. doi:10.1089/neu.2012.2371

    Article  PubMed Central  PubMed  Google Scholar 

  135. Zimmermann M (1997) Endothelin in cerebral vasospasm. Clinical and experimental results. J Neurosurg Sci 41(2):139–151

    CAS  PubMed  Google Scholar 

  136. Kallakuri S, Kreipke CW, Schafer PC, Schafer SM, Rafols JA (2010) Brain cellular localization of endothelin receptors A and B in a rodent model of diffuse traumatic brain injury. Neuroscience 168(3):820–830. doi:10.1016/j.neuroscience.2010.01.018

    Article  CAS  PubMed  Google Scholar 

  137. Barnes K, Turner AJ (1997) The endothelin system and endothelin-converting enzyme in the brain: molecular and cellular studies. Neurochem Res 22(8):1033–1040

    Article  CAS  PubMed  Google Scholar 

  138. Dehouck MP, Vigne P, Torpier G, Breittmayer JP, Cecchelli R, Frelin C (1997) Endothelin-1 as a mediator of endothelial cell-pericyte interactions in bovine brain capillaries. J Cereb Blood Flow Metab 17(4):464–469. doi:10.1097/00004647-199704000-00012

    Article  CAS  PubMed  Google Scholar 

  139. Hama H, Kasuya Y, Sakurai T, Yamada G, Suzuki N, Masaki T, Goto K (1997) Role of endothelin-1 in astrocyte responses after acute brain damage. J Neurosci Res 47(6):590–602

    Article  CAS  PubMed  Google Scholar 

  140. McKenzie AL, Hall JJ, Aihara N, Fukuda K, Noble LJ (1995) Immunolocalization of endothelin in the traumatized spinal cord: relationship to blood-spinal cord barrier breakdown. J Neurotrauma 12(3):257–268

    Article  CAS  PubMed  Google Scholar 

  141. Westmark R, Noble LJ, Fukuda K, Aihara N, McKenzie AL (1995) Intrathecal administration of endothelin-1 in the rat: impact on spinal cord blood flow and the blood-spinal cord barrier. Neurosci Lett 192(3):173–176

    Article  CAS  PubMed  Google Scholar 

  142. Giaid A, Gibson SJ, Ibrahim BN, Legon S, Bloom SR, Yanagisawa M, Masaki T, Varndell IM et al (1989) Endothelin 1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia. Proc Natl Acad Sci U S A 86(19):7634–7638

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Peters CM, Rogers SD, Pomonis JD, Egnaczyk GF, Keyser CP, Schmidt JA, Ghilardi JR, Maggio JE et al (2003) Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis. Exp Neurol 180(1):1–13

    Article  CAS  PubMed  Google Scholar 

  144. Siren AL, Knerlich F, Schilling L, Kamrowski-Kruck H, Hahn A, Ehrenreich H (2000) Differential glial and vascular expression of endothelins and their receptors in rat brain after neurotrauma. Neurochem Res 25(7):957–969

    Article  CAS  PubMed  Google Scholar 

  145. MacCumber MW, Ross CA, Snyder SH (1990) Endothelin in brain: receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci U S A 87(6):2359–2363

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  146. Bertsch T, Kuehl S, Muehlhauser F, Walter S, Hodapp B, Rossol S, Schmeck J, Ragoschke A et al (2001) Source of endothelin-1 in subarachnoid hemorrhage. Clin Chem Lab Med: CCLM/FESCC 39(4):341–345. doi:10.1515/CCLM.2001.053

    CAS  Google Scholar 

  147. Yamashita K, Kataoka Y, Sakurai-Yamashita Y, Shigematsu K, Himeno A, Niwa M, Taniyama K (2000) Involvement of glial endothelin/nitric oxide in delayed neuronal death of rat hippocampus after transient forebrain ischemia. Cell Mol Neurobiol 20(5):541–551

    Article  CAS  PubMed  Google Scholar 

  148. Salzman SK, Acosta R, Beck G, Madden J, Boxer B, Ohlstein EH (1996) Spinal endothelin content is elevated after moderate local trauma in the rat to levels associated with locomotor dysfunction after intrathecal injection. J Neurotrauma 13(2):93–101

    Article  CAS  PubMed  Google Scholar 

  149. Uesugi M, Kasuya Y, Hayashi K, Goto K (1998) SB209670, a potent endothelin receptor antagonist, prevents or delays axonal degeneration after spinal cord injury. Brain Res 786(1-2):235–239

    Article  CAS  PubMed  Google Scholar 

  150. Weinzierl M, Mautes AE, Whetstone W, Lin Y, Noble-Haeusslein LJ (2004) Endothelin-mediated induction of heme oxygenase-1 in the spinal cord is attenuated in transgenic mice overexpressing superoxide dismutase. Brain Res 1030(1):125–132. doi:10.1016/j.brainres.2004.09.060

    Article  CAS  PubMed  Google Scholar 

  151. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Lee JY, Kim HS, Choi HY, Oh TH, Ju BG, Yune TY (2012) Valproic acid attenuates blood-spinal cord barrier disruption by inhibiting matrix metalloprotease-9 activity and improves functional recovery after spinal cord injury. J Neurochem 121(5):818–829. doi:10.1111/j.1471-4159.2012.07731.x

    Article  CAS  PubMed  Google Scholar 

  153. Fang B, Li XQ, Bi B, Tan WF, Liu G, Zhang Y, Ma H (2015) Dexmedetomidine attenuates blood-spinal cord barrier disruption induced by spinal cord ischemia reperfusion injury in rats. Cell Physiol Biochem 36(1):373–383. doi:10.1159/000430107

    Article  CAS  PubMed  Google Scholar 

  154. Sharma HS, Badgaiyan RD, Alm P, Mohanty S, Wiklund L (2005) Neuroprotective effects of nitric oxide synthase inhibitors in spinal cord injury-induced pathophysiology and motor functions: an experimental study in the rat. Ann N Y Acad Sci 1053:422–434. doi:10.1196/annals.1344.037

    Article  CAS  PubMed  Google Scholar 

  155. 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. Biochim Biophys Acta 1842(12 Pt A):2403–2412. doi:10.1016/j.bbadis.2014.09.006

    Article  CAS  PubMed  Google Scholar 

  156. Tian DS, Liu JL, Xie MJ, Zhan Y, Qu WS, Yu ZY, Tang ZP, Pan DJ et al (2009) Tamoxifen attenuates inflammatory-mediated damage and improves functional outcome after spinal cord injury in rats. J Neurochem 109(6):1658–1667. doi:10.1111/j.1471-4159.2009.06077.x

    Article  CAS  PubMed  Google Scholar 

  157. Repici M, Chen X, Morel MP, Doulazmi M, Sclip A, Cannaya V, Veglianese P, Kraftsik R et al (2012) Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury. Neurobiol Dis 46(3):710–721. doi:10.1016/j.nbd.2012.03.014

    Article  CAS  PubMed  Google Scholar 

  158. Tonai T, Shiba K, Taketani Y, Ohmoto Y, Murata K, Muraguchi M, Ohsaki H, Takeda E et al (2001) A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in rats. J Neurochem 78(5):1064–1072

    Article  CAS  PubMed  Google Scholar 

  159. Fan Z, Cao Y, Zhang Z, Wang Y, Yu D, Zhang M, Mei X, Lu G (2012) Effect of aminoguanidine on spinal cord edema of acute spinal cord injury in rats. Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery 26(8):984–988

    CAS  PubMed  Google Scholar 

  160. Fang B, Wang H, Sun XJ, Li XQ, Ai CY, Tan WF, White PF, Ma H (2013) Intrathecal transplantation of bone marrow stromal cells attenuates blood-spinal cord barrier disruption induced by spinal cord ischemia-reperfusion injury in rabbits. J Vasc Surg 58(4):1043–1052. doi:10.1016/j.jvs.2012.11.087

    Article  PubMed  Google Scholar 

  161. Fang B, Li XM, Sun XJ, Bao NR, Ren XY, Lv HW, Ma H (2013) Ischemic preconditioning protects against spinal cord ischemia-reperfusion injury in rabbits by Attenuating Blood Spinal Cord barrier disruption. Int J Mol Sci 14(5):10343–10354. doi:10.3390/ijms140510343

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  162. 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. doi:10.1210/en.2014-1832

    Article  CAS  PubMed  Google Scholar 

  163. Wu Q, Jing Y, Yuan X, Zhang X, Li B, Liu M, Wang B, Li H et al (2014) Melatonin treatment protects against acute spinal cord injury-induced disruption of blood spinal cord barrier in mice. J Mol Neurosci: MN 54(4):714–722. doi:10.1007/s12031-014-0430-4

    Article  CAS  PubMed  Google Scholar 

  164. Li XQ, Cao XZ, Wang J, Fang B, Tan WF, Ma H (2014) Sevoflurane preconditioning ameliorates neuronal deficits by inhibiting microglial MMP-9 expression after spinal cord ischemia/reperfusion in rats. Mol Brain 7:69. doi:10.1186/s13041-014-0069-7

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  165. Li Y-Q, Ballinger JR, Nordal RA, Su Z-F, Wong CS (2001) Hypoxia in radiation-induced blood-spinal cord barrier breakdown. Cancer Res 61(8):3348–3354

    CAS  PubMed  Google Scholar 

  166. Kiyatkin EA, Sharma HS (2015) Not just the brain: methamphetamine disrupts blood-spinal cord barrier and induces acute glial activation and structural damage of spinal cord cells. CNS Neurol Disord Drug Targets 14(2):282–294

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Nyberg F, Sharma HS (2002) Repeated topical application of growth hormone attenuates blood-spinal cord barrier permeability and edema formation following spinal cord injury: an experimental study in the rat using Evans blue, ([125])I-sodium and lanthanum tracers. Amino Acids 23(1-3):231–239. doi:10.1007/s00726-001-0134-2

    Article  CAS  PubMed  Google Scholar 

  168. Matsushita T, Lankford KL, Arroyo EJ, Sasaki M, Neyazi M, Radtke C, Kocsis JD (2015) Diffuse and persistent blood-spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells. Exp Neurol 267:152–164. doi:10.1016/j.expneurol.2015.03.001

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by a grant of the National Research Foundation of Korea (NRF) (NRF-2014R1A1A2059118) and the Ministry of Science, ICT and Future Planning (NRF-2013R1A2A1A09013980).

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Authors and Affiliations

  1. Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea

    Hemant Kumar & Inbo Han

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

    Alexander E. Ropper

  3. Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea

    Soo-Hong Lee

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  1. Hemant Kumar
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Kumar, H., Ropper, A.E., Lee, SH. et al. Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury. Mol Neurobiol 54, 3578–3590 (2017). https://doi.org/10.1007/s12035-016-9910-6

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