Clin Orthop Surg.  2017 Mar;9(1):1-9. 10.4055/cios.2017.9.1.1.

Spinal Cord Injury and Related Clinical Trials

Affiliations
  • 1Department of Orthopaedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. boscoa@catholic.ac.kr

Abstract

Spinal cord injury (SCI) has been considered an incurable condition and it often causes devastating sequelae. In terms of the pathophysiology of SCI, reducing secondary damage is the key to its treatment. Various researches and clinical trials have been performed, and some of them showed promising results; however, there is still no gold standard treatment with sufficient evidence. Two therapeutic concepts for SCI are neuroprotective and neuroregenerative strategies. The neuroprotective strategy modulates the pathomechanism of SCI. The purpose of neuroprotective treatment is to minimize secondary damage following direct injury. The aim of neuroregenerative treatment is to enhance the endogenous regeneration process and to alter the intrinsic barrier. With advancement in biotechnology, cell therapy using cell transplantation is currently under investigation. This review discusses the pathophysiology of SCI and introduces the therapeutic candidates that have been developed so far.

Keyword

Spinal cord injuries; Neuroprotective; Neuroregenerative; Pathophysiology

MeSH Terms

Axons/physiology
*Cell Transplantation
Clinical Trials as Topic
Humans
Hypothermia, Induced
Myelin Sheath/metabolism
*Nerve Regeneration
Neuroprotection
Neuroprotective Agents/*therapeutic use
Spinal Cord/*physiopathology
Spinal Cord Injuries/*physiopathology/*therapy
Neuroprotective Agents

Figure

  • Fig. 1 Pathophysiological events occurring after spinal cord injury.

  • Fig. 2 Pathologic consequences of spinal cord injury. Clinical trials have been attempted for neuroprotection to determine each pathomechanism of spinal cord injury. IL: interleukin, TNF: tumor necrosis factor, NMDA: N-methyl-D-aspartate.


Cited by  1 articles

The Importance of Early Surgical Decompression for Acute Traumatic Spinal Cord Injury
Dong-Yeong Lee, Young-Jin Park, Sang-Youn Song, Sun-Chul Hwang, Kun-Tae Kim, Dong-Hee Kim
Clin Orthop Surg. 2018;10(4):448-454.    doi: 10.4055/cios.2018.10.4.448.


Reference

1. Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine (Phila Pa 1976). 2001; 26:24 Suppl. S2–S12.
Article
2. Ho CH, Wuermser LA, Priebe MM, Chiodo AE, Scelza WM, Kirshblum SC. Spinal cord injury medicine: 1. epidemiology and classification. Arch Phys Med Rehabil. 2007; 88:3 Suppl 1. S49–S54.
Article
3. Vialle R, Levassor N, Rillardon L, Templier A, Skalli W, Guigui P. Radiographic analysis of the sagittal alignment and balance of the spine in asymptomatic subjects. J Bone Joint Surg Am. 2005; 87(2):260–267.
Article
4. Barron KD, Hirano A, Araki S, Terry RD. Experiences with metastatic neoplasms involving the spinal cord. Neurology. 1959; 9(2):91–106.
Article
5. Gerszten PC, Welch WC. Current surgical management of metastatic spinal disease. Oncology (Williston Park). 2000; 14(7):1013–1024.
6. Schaberg J, Gainor BJ. A profile of metastatic carcinoma of the spine. Spine (Phila Pa 1976). 1985; 10(1):19–20.
Article
7. Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus. 2008; 25(5):E2.
Article
8. Kwon BK, Tetzlaff W, Grauer JN, Beiner J, Vaccaro AR. Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J. 2004; 4(4):451–464.
Article
9. Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 1991; 75(1):15–26.
Article
10. Tator CH, Koyanagi I. Vascular mechanisms in the pathophysiology of human spinal cord injury. J Neurosurg. 1997; 86(3):483–492.
Article
11. Schanne FA, Kane AB, Young EE, Farber JL. Calcium dependence of toxic cell death: a final common pathway. Science. 1979; 206(4419):700–702.
Article
12. Ha KY, Carragee E, Cheng I, Kwon SE, Kim YH. Pregabalin as a neuroprotector after spinal cord injury in rats: biochemical analysis and effect on glial cells. J Korean Med Sci. 2011; 26(3):404–411.
Article
13. Ha KY, Kim YH, Rhyu KW, Kwon SE. Pregabalin as a neuroprotector after spinal cord injury in rats. Eur Spine J. 2008; 17(6):864–872.
Article
14. Li S, Stys PK. Mechanisms of ionotropic glutamate receptor-mediated excitotoxicity in isolated spinal cord white matter. J Neurosci. 2000; 20(3):1190–1198.
Article
15. Li S, Mealing GA, Morley P, Stys PK. Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport. J Neurosci. 1999; 19(14):RC16.
Article
16. Park E, Velumian AA, Fehlings MG. The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma. 2004; 21(6):754–774.
Article
17. Donnelly DJ, Popovich PG. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp Neurol. 2008; 209(2):378–388.
Article
18. Xiong Y, Rabchevsky AG, Hall ED. Role of peroxynitrite in secondary oxidative damage after spinal cord injury. J Neurochem. 2007; 100(3):639–649.
Article
19. Pineau I, Lacroix S. Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. J Comp Neurol. 2007; 500(2):267–285.
Article
20. Fleming JC, Norenberg MD, Ramsay DA, et al. The cellular inflammatory response in human spinal cords after injury. Brain. 2006; 129(Pt 12):3249–3269.
Article
21. Beattie MS, Hermann GE, Rogers RC, Bresnahan JC. Cell death in models of spinal cord injury. Prog Brain Res. 2002; 137:37–47.
22. Stys PK, Lipton SA. White matter NMDA receptors: an unexpected new therapeutic target? Trends Pharmacol Sci. 2007; 28(11):561–566.
Article
23. Totoiu MO, Keirstead HS. Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol. 2005; 486(4):373–383.
Article
24. Kakulas BA. Neuropathology: the foundation for new treatments in spinal cord injury. Spinal Cord. 2004; 42(10):549–563.
Article
25. Lasiene J, Shupe L, Perlmutter S, Horner P. No evidence for chronic demyelination in spared axons after spinal cord injury in a mouse. J Neurosci. 2008; 28(15):3887–3896.
Article
26. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000; 32(1):1–14.
Article
27. Williams A, Piaton G, Lubetzki C. Astrocytes: friends or foes in multiple sclerosis? Glia. 2007; 55(13):1300–1312.
28. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004; 24(9):2143–2155.
Article
29. Herrmann JE, Imura T, Song B, et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci. 2008; 28(28):7231–7243.
Article
30. Pan JZ, Ni L, Sodhi A, Aguanno A, Young W, Hart RP. Cytokine activity contributes to induction of inflammatory cytokine mRNAs in spinal cord following contusion. J Neurosci Res. 2002; 68(3):315–322.
Article
31. Black P, Markowitz RS. Experimental spinal cord injury in monkeys: comparison of steroids and local hypothermia. Surg Forum. 1971; 22:409–411.
32. Campbell JB, DeCrescito V, Tomasula JJ, Demopoulos HB, Flamm ES, Ransohoff J. Experimental treatment of spinal cord contusion in the cat. Surg Neurol. 1973; 1(2):102–106.
33. Green BA, Kahn T, Klose KJ. A comparative study of steroid therapy in acute experimental spinal cord injury. Surg Neurol. 1980; 13(2):91–97.
34. Bracken MB, Shepard MJ, Hellenbrand KG, et al. Methylprednisolone and neurological function 1 year after spinal cord injury: results of the National Acute Spinal Cord Injury Study. J Neurosurg. 1985; 63(5):704–713.
Article
35. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990; 322(20):1405–1411.
Article
36. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial: National Acute Spinal Cord Injury Study. JAMA. 1997; 277(20):1597–1604.
Article
37. Hurlbert RJ, Hadley MN, Walters BC. Pharmacological therapy for acute spinal cord injury. Neurosurgery. 2013; 72:Suppl 2. 93–105.
Article
38. Bose B, Osterholm JL, Kalia M. Ganglioside-induced regeneration and reestablishment of axonal continuity in spinal cord-transected rats. Neurosci Lett. 1986; 63(2):165–169.
Article
39. Geisler FH, Dorsey FC, Coleman WP. Recovery of motor function after spinal-cord injury: a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med. 1991; 324(26):1829–1838.
Article
40. Geisler FH. GM-1 ganglioside and motor recovery following human spinal cord injury. J Emerg Med. 1993; 11:Suppl 1. 49–55.
41. Geisler FH, Coleman WP, Grieco G, Poonian D. Sygen Study Group. The Sygen multicenter acute spinal cord injury study. Spine (Phila Pa 1976). 2001; 26:24 Suppl. S87–S98.
Article
42. Wrathall JR, Teng YD, Choiniere D. Amelioration of functional deficits from spinal cord trauma with systemically administered NBQX, an antagonist of non-N-methyl-D-aspartate receptors. Exp Neurol. 1996; 137(1):119–126.
Article
43. Wrathall JR, Teng YD, Marriott R. Delayed antagonism of AMPA/kainate receptors reduces long-term functional deficits resulting from spinal cord trauma. Exp Neurol. 1997; 145(2 Pt 1):565–573.
Article
44. Tadie M, d'Arbigny P, Mathe JF, et al. Acute spinal cord injury: early care and treatment in a multicenter study with gacyclidine. Soc Neurosci Abstr. 1999; 25(1-2):1090.
45. Boran BO, Colak A, Kutlay M. Erythropoietin enhances neurological recovery after experimental spinal cord injury. Restor Neurol Neurosci. 2005; 23(5-6):341–345.
46. King VR, Averill SA, Hewazy D, Priestley JV, Torup L, Michael-Titus AT. Erythropoietin and carbamylated erythropoietin are neuroprotective following spinal cord hemisection in the rat. Eur J Neurosci. 2007; 26(1):90–100.
Article
47. Yazihan N, Uzuner K, Salman B, Vural M, Koken T, Arslantas A. Erythropoietin improves oxidative stress following spinal cord trauma in rats. Injury. 2008; 39(12):1408–1413.
Article
48. Okutan O, Solaroglu I, Beskonakli E, Taskin Y. Recombinant human erythropoietin decreases myeloperoxidase and caspase-3 activity and improves early functional results after spinal cord injury in rats. J Clin Neurosci. 2007; 14(4):364–368.
Article
49. Fehlings MG, Tator CH, Linden RD. The effect of nimodipine and dextran on axonal function and blood flow following experimental spinal cord injury. J Neurosurg. 1989; 71(3):403–416.
Article
50. Petitjean ME, Pointillart V, Dixmerias F, et al. Medical treatment of spinal cord injury in the acute stage. Ann Fr Anesth Reanim. 1998; 17(2):114–122.
51. Cardenas DD, Ditunno J, Graziani V, et al. Phase 2 trial of sustained-release fampridine in chronic spinal cord injury. Spinal Cord. 2007; 45(2):158–168.
Article
52. Yune TY, Lee JY, Jung GY, et al. Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. J Neurosci. 2007; 27(29):7751–7761.
Article
53. Casha S, Zygun D, McGowan MD, Bains I, Yong VW, Hurlbert RJ. Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain. 2012; 135(Pt 4):1224–1236.
Article
54. Ok JH, Kim YH, Ha KY. Neuroprotective effects of hypothermia after spinal cord injury in rats: comparative study between epidural hypothermia and systemic hypothermia. Spine (Phila Pa 1976). 2012; 37(25):E1551–E1559.
55. Ha KY, Kim YH. Neuroprotective effect of moderate epidural hypothermia after spinal cord injury in rats. Spine (Phila Pa 1976). 2008; 33(19):2059–2065.
Article
56. Dididze M, Green BA, Dietrich WD, Vanni S, Wang MY, Levi AD. Systemic hypothermia in acute cervical spinal cord injury: a case-controlled study. Spinal Cord. 2013; 51(5):395–400.
Article
57. Duncan ID, Brower A, Kondo Y, Curlee JF Jr, Schultz RD. Extensive remyelination of the CNS leads to functional recovery. Proc Natl Acad Sci U S A. 2009; 106(16):6832–6836.
Article
58. Liebetanz D, Merkler D. Effects of commissural de- and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis. Exp Neurol. 2006; 202(1):217–224.
Article
59. Waxman SG. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci. 2006; 7(12):932–941.
Article
60. Bretzner F, Plemel JR, Liu J, Richter M, Roskams AJ, Tetzlaff W. Combination of olfactory ensheathing cells with local versus systemic cAMP treatment after a cervical rubrospinal tract injury. J Neurosci Res. 2010; 88(13):2833–2846.
Article
61. Ramer LM, Richter MW, Roskams AJ, Tetzlaff W, Ramer MS. Peripherally-derived olfactory ensheathing cells do not promote primary afferent regeneration following dorsal root injury. Glia. 2004; 47(2):189–206.
Article
62. Ramer LM, Au E, Richter MW, Liu J, Tetzlaff W, Roskams AJ. Peripheral olfactory ensheathing cells reduce scar and cavity formation and promote regeneration after spinal cord injury. J Comp Neurol. 2004; 473(1):1–15.
Article
63. Biernaskie J, Sparling JS, Liu J, et al. Skin-derived precursors generate myelinating Schwann cells that promote remyelination and functional recovery after contusion spinal cord injury. J Neurosci. 2007; 27(36):9545–9559.
Article
64. Nistor GI, Totoiu MO, Haque N, Carpenter MK, Keirstead HS. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia. 2005; 49(3):385–396.
Article
65. Keirstead HS, Nistor G, Bernal G, et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J Neurosci. 2005; 25(19):4694–4705.
Article
66. Horky LL, Galimi F, Gage FH, Horner PJ. Fate of endogenous stem/progenitor cells following spinal cord injury. J Comp Neurol. 2006; 498(4):525–538.
Article
67. Lytle JM, Chittajallu R, Wrathall JR, Gallo V. NG2 cell response in the CNP-EGFP mouse after contusive spinal cord injury. Glia. 2009; 57(3):270–285.
Article
68. Barres BA, Schmid R, Sendnter M, Raff MC. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development. 1993; 118(1):283–295.
Article
69. Tripathi RB, McTigue DM. Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats. J Comp Neurol. 2008; 510(2):129–144.
Article
70. Caroni P, Schwab ME. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron. 1988; 1(1):85–96.
Article
71. Caroni P, Schwab ME. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. J Cell Biol. 1988; 106(4):1281–1288.
Article
72. Barritt AW, Davies M, Marchand F, et al. Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury. J Neurosci. 2006; 26(42):10856–10867.
Article
73. Shields LB, Zhang YP, Burke DA, Gray R, Shields CB. Benefit of chondroitinase ABC on sensory axon regeneration in a laceration model of spinal cord injury in the rat. Surg Neurol. 2008; 69(6):568–577.
Article
74. Kim JW, Ha KY, Molon JN, Kim YH. Bone marrow-derived mesenchymal stem cell transplantation for chronic spinal cord injury in rats: comparative study between intralesional and intravenous transplantation. Spine (Phila Pa 1976). 2013; 38(17):E1065–E1074.
75. Kim DH, Yoo KH, Yim YS, et al. Cotransplanted bone marrow derived mesenchymal stem cells (MSC) enhanced engraftment of hematopoietic stem cells in a MSC-dose dependent manner in NOD/SCID mice. J Korean Med Sci. 2006; 21(6):1000–1004.
Article
76. Panayiotou E, Malas S. Adult spinal cord ependymal layer: a promising pool of quiescent stem cells to treat spinal cord injury. Front Physiol. 2013; 4:340.
Article
77. Lee HJ, Wu J, Chung J, Wrathall JR. SOX2 expression is upregulated in adult spinal cord after contusion injury in both oligodendrocyte lineage and ependymal cells. J Neurosci Res. 2013; 91(2):196–210.
Article
78. Lacroix S, Hamilton LK, Vaugeois A, et al. Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions. PLoS One. 2014; 9(1):e85916.
Article
Full Text Links
  • CIOS
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr