Pharmacological Treatment of Acute Spinal Cord Injuries In The Light Of Recent Developments

Abstract

Spinal injuries represent a significant public health issue with both individual and societal implications due to its potential to result in long-term or permanent disability and death. Today, notwithstanding the comprehensive elucidation of the mechanism of injury in its all aspects and breakthroughs in early diagnosis techniques and treatment, spinal injuries still retain their devastating nature. Although many agents hypothesized to possess neuroprotective and neuroregenerative properties have been demonstrated to be effective in the experiments, research involving human subjects is still in progress, offering promising developments. Methylprednisolone at a high dose is the most extensively investigated therapeutic for acute spinal injuries. Despite significant controversy, it remains a viable treatment option. It is anticipated that combining stem cell transplantation with multiple pharmacological agents will yield more favorable outcomes.

Keywords

• spinal injuries
• pharmacological Agents
• Stem Cell Transplantation

References

1. 1. Ahmad, F.U., Wang, M.Y., & Levi, A.D. (2014). Hypothermia for acute spinal cord injury–a review. World Neurosurgery, 82(1–2):207-14. https://doi.org/10.1016/j.wneu.2013.01.008.
2. 2. Ahuja, C.S., Martin, A.R., & Fehlings, M. (2016). Recent advances in managing a spinal cord injury secondary to trauma. F1000Res, 27;5: F1000 Faculty Rev-1017. https://doi.org/ 10.12688/f1000research.7586.1. 3. Alibai, E.A., Baghban, F., Farrokhi, M.R., Mohebali, N., & Ashraf, M.H. (2015). Effects of human erythropoietin on functional outcome of patients with traumatic cervical cord injury; a pilot randomised clinical trial. Bull Emerg Trauma, 3(3):79-85. https://doi.org/ 10.7508/beat.2015.03.002.
3. 4. Allan, R.M., Aleksanderek, I., & Fehlings, G.M. (2015). Diagnosis and acute management of spinal cord injury: Current best practices and emerging therapies. Curr Trauma Rep., 1:169-181. https://doi.org/10.1007/s11910-019-0984-1.
4. 5. Antonic, A., Sena, E. S., Lees, J. S., Wills, T. E., Skeers, P., Batchelor, P. E., Batchelor, P.E., Macleod, M.R., & Howells, D.W. (2013). Stem cell transplantation in traumatic spinal cord injury: a systematic review and meta-analysis of animal studies. PLoS biology, 11(12), e1001738. https://doi.org/10.1371/journal.pbio.1001738.
5. 6. Barnabé-Heider, F., & Frisén, J. (2008). Stem cells for spinal cord repair. Cell stem cell, 3(1), 16-24.https://doi.org/10.1016/j.stem.2008.06.011.
6. 7. Boyalı, O., Cıvelek, E., & Kabataş, S. (2020). Travmatik Omurilik Yaralanmasında Konservatif Tedavi (Güncel Farmakolojik Tedavi Yöntemleri). Türk Nöroşirürji Dergisi, 30(3), 466-474. https://doi.org/ norosirurji.dergisi.org/pdf.php?&id=1591.
7. 8. Bracken, M.B., Shepard, M.J., & Hellenbrand, K.G. (1985). Methylprednisolone and neurological function 1 year after spinal cord injury. Results of the National Acute Spinal Cord Injury Study. J Neurosurg, 63(5):704-713. https://doi.org/10.3171/jns.1985.63.5.0704.
8. 9. Bracken, M.B., Shepard, M.J., Collins, W.F., Holford, T.R., Young, W., & Baskin, D.S. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinalcord injury: Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med, 322(20):1405-1411. https://doi.org/10.1056/nejm199005173222001.

9. 10. Bracken M.B., Shepard M.J., &Holford T.R. (1997). 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, 277(20):1597–1604. https://doi.org/10.1001/JAMA.1997.03540440031029.
10. 11. Bradbury, E.J., Moon, L., Popat, R., King, V.R., Bennett, G.S., Patel, P.N., Fawcett, J.W., & McMahon, S.B. (2002). Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature, 416: 636–40. https://doi.org/10.1038/416636a.
11. 12. Can, H., Aydoseli, A., Gömleksiz, C., Göker, B., Altunrende, M.E., Dolgun, M., & Sencer, A. (2017). Combined and individual use of pancaspase inhibitor Q-VD-OPh and NMDA receptor antagonist riluzole in experimental spinal cord injury. Ulus Travma Acil Cerrahi Derg., 23(6):452-8. https://doi.org/10.5505/tjtes.2017.09694.
12. 13. Can, H., Savrunlu, E.C., & Kabataş, S. (2021). Omurilik Yaralanmalarında Medikal Tedavi. J Nervous Sys Surgery, 7(1):8-13. https://doi.org/10.5222/sscd.2021.80764.
13. 14. Canseco, J.A., Karamian, B.A., Bowles, D.R., Markowitz, M.P., DiMaria, S.L., Semenza, N.C., Leibensperger, M.R., Smith, M.L., & Vaccaro, A.R. (2021). Updated Review: The Steroid Controversy for Management of Spinal Cord Injury. World Neurosurg, 150:1-8. https://doi.org/10.1016/j.wneu.2021.02.116.
14. 15. Casha, S., Zygun, D., McGowan, M.D., Bains, I., Yong, V.W., & Hurlbert, R.J. (2012). Results of a phase II placebo-controlled randomized trial of minocycline in acute spinal cord injury. Brain, 135(Pt 4):1224–36. https://doi.org/ 10.1093/brain/aws072.
15. 16. Chavasiri, C., Suriyachat, N., Luksanapruksa, P., Wilartratsami, S., & Chavasiri, S. (2022). Incidence of and factors associated with hyponatremia in traumatic cervical spinal cord injury patients. Spinal cord series and cases, 8(1), 15. https://doi.org/10.1038/s41394-022-00475-0.
16. 17. Chen, M.S., Huber, A.B., & van der Haar, M.E. (2000). Nogo- A is a myelin- associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature, 403(6768):434-439. https://doi.org/10.1038/35000219.
17. 18. Coutinho, A.E., & Chapman, K.E. (2011). The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol, 335(1):2-13. https://doi.org/10.1016/j.mce.2010.04.005.
18. 19. Cozzens, J.W., Prall, J.A., & Holly, L. (2013). The 2012 Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injury. Neurosurgery, 72 Suppl 2:2-3. https://doi.org/ 10.1227/neu.0b013e3182772981.
19. 20. De Laporte, L., des Rieux, A., Tuinstra, H.M., Zelivyanskaya, M.L., De Clerck, N.M., Postnov, A.A., Préat, V., & Shea, L.D. (2011). Vascular endothelial growth factor and fibroblast growth factor 2 delivery from spinal cord bridges to enhance angiogenesis following injury. J Biomed Mater Res A., 1;98(3):372-82. https://doi.org/10.1002/jbm.a.33112.
20. 21. Devivo, M.J. (2012). Epidemiology of traumatic spinal cord injury: trends and future implications. Spinal Cord, 50:365–72. https://doi.org/10.1038/sc.2011.178.
21. 22. Dididze, M., Green, B., Dietrich, W.D., Vanni, S., Wang, M.Y., & Levi, A.D. (2013) Systemic hypothermia in acute cervical spinal cord injury: a case-controlled study. Spinal Cord 51, 395–400. https://doi.org/10.1038/sc.2012.161.
22. 23. Dietrich, W.D., Levi, A.D., Wang, M., & Green, B.A. (2011). Hypothermic treatment for acute spinal cord injury. Neurotherapeutics,8:229-39. https://doi.org/10.1007/s13311-011-0035-3.
23. 24. Donnelly, E. M., Lamanna, J., & Boulis, N. M. (2012). Stem cell therapy for the spinal cord. Stem Cell Research & Therapy, 3, 1-9. https://doi.org/10.1186/scrt115.
24. 25. Eli, I., Lerner, D. P., & Zoher, G. (2021). Acute Traumatic Spinal Cord Injury. Neurol Clin., 39:471–488. https://doi.org/10.1016/j.ncl.2021.02.004.
25. 26. Fehlings, M.G., Tetreault, L.A., Wilson J.R., Kwon, B.K., Burns, A.S., Martin, A.R., & et al. (2017). A clinical practice guideline for the management of acute spinal cord injury: introduction, rationale, and scope. Global Spine J, 7(3 Suppl):84S–94S. https://doi.org/10.1177/2192568217703387.
26. 27. Fehlings, M.G., Theodore, N., & Harrop, J. (2011). A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury. J Neurotrauma, 28(5):787–796. https://doi.org/10.1089/neu.2011.1765.
27. 28. Festoff, B.W., Ameenuddin, S., Arnold, P.M., Wong, A., Santacruz, K.S., & Citron, B.A. (2006). Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem, 97:1314-26. https://doi.org/10.1111/j.1471-4159.2006.03799.x.
28. 29. Forgione, N., & Fehlings, M.G. (2014). Rho-ROCK inhibition in the treatment of spinal cord injury. World Neurosurg., 2(3-4):e535-9. https://doi.org/10.1016/j.wneu.2013.01.009.
29. 30. Ganjeifar, B., Rezaee, H., Keykhosravi, E., Tavallaii, A., Bahadorkhan, G., Nakhaei, M., & Abouei Mehrizi, M.A. (2021). The effect of combination therapy with erythropoietin and methylprednisolone in patients with traumatic cervical spinal cord injury: a pilot randomized controlled trial. Spinal Cord., 59(3):347-53. https://doi.org/10.1038/s41393-020-00604-2.
30. 31. Gustorff, B., Dorner, T., Likar, R., Grisold, W., Lawrence, K., Schwarz, F., & Rieder, A. (2008). Prevalence of self‐reported neuropathic pain and impact on quality of life: a prospective representative survey. Acta Anaesthesiologica Scandinavica, 52(1), 132-136. https://doi.org/10.1111/j.1399-6576.2007.01486.x.
31. 32. Hadley, M.N., Walters, B.C., Grabb, P.A., Oyesiku, N.M., Przybylski, G.J., Resnick, D.K., & et al. (2002). Blood pressure management after acute spinal cord injury. Neurosurgery, 50: 58-62. https://doi.org/10.1097/00006123-200203001-00012.
32. 33. Hadley, M.N., & Walters, B.C. (2013). Introduction to the guidelines for the management of acute cervical spine and spinal cord injuries. Neurosurgery, 72 Suppl 2:5-16. https://doi.org/ 10.1227/neu.0b013e3182773549.
33. 34. Hansebout, R.R., & Hansebout, C.R. (2014). Local cooling for traumatic spinal cord injury: outcomes in 20 patients and review of the literature. J Neurosurg Spine, 20(5):550-61. https://doi.org/10.3171/2014.2.SPINE13318.
34. 35. Huang, H., Young, W., Skaper, S., Chen, L., Moviglia, G., Saberi, H., Al-Zoubi, Z., Sharma, H.S., Muresanu, D., Sharma, A., El Masry, W., & Feng, S. (2019). International Association of Neurorestoratology and The Chinese Association of Neurorestoratology. Clinical Neurorestorative Therapeutic Guidelines for Spinal Cord Injury (IANR/CANR version 2019). J Orthop Translat., 11;20:14-24. https://doi.org/10.1016/j.jot.2019.10.006.
35. 36. Hurlbert, R.J., Hadley, M.N., Walters, B.C., Aarabi, B., Dhall, S.S., Gelb, D.E., Rozzelle, C.J., Ryken T.C., &Theodore, N. (2015). Pharmacological therapy for acute spinal cord injury. Neurosurgery,76(Suppl;1): 71–83. https://doi.org/10.1227/01.neu.0000462080.04196.f7.
36. 37. Jutzeler, C.R., Bourguignon, L., Tong, B., Ronca, E., Bailey, E., Harel, N.Y., Geisler, F., Ferguson, A.R., Kwon, B.K., Cragg, J.J., Grassner, L., & Kramer, J.L.K. (2023). Pharmacological management of acute spinal cord injury: a longitudinal multi-cohort observational study. Sci Rep, 3;13(1):5434. https://doi.org/10.1038/s41598-023-31773-8.
37. 38. Karsy, M., &Hawryluk, G. (2019). Modern Medical Management of Spinal Cord Injury. Current Neurology and Neuroscience Reports, 19: 65. https://doi.org/10.1007/s11910-019-0984-1.
38. 39. Kitamura, K., Fujiyoshi, K., Yamane, J., Toyota, F., Hikishima, K., Nomura, T., Funakoshi, H., Nakamura, T., Aoki, M., Toyama, Y., Okano, H., & Nakamura, M. (2011). Human hepatocyte growth factor promotes functional recovery in primates after spinal cord injury. PLoS One, 6(11): e27706. https://doi.org/10.1371/journal.pone.0027706.
39. 40. Kurland, D.B., Tosun C, Pampori A, Karimy, J.K., Caffes, N.M., Gerzanich, V., & Simard, J.M. (2013). Glibenclamide for the treatment of acute CNS injury. Pharmaceuticals (Basel), 6(10):1287–303. https://doi.org/10.3390/ph6101287.
40. 41. Kwon, B.K., Mann, C., Sohn, H.M., Hilibrand, A.S., Phillips, F.M., Wang, J.C., & Fehlings, M.G. Hypothermia for spinal cord injury. Spine J. 2008 Nov-Dec;8(6):859-74. https://doi.org/10.1016/j.spinee.2007.12.006.
41. 42. Kwon, B.K, Roy, J., Lee, J.H., Okon, E., Zhang, H., Marx, J.C., & Kindy, M.S. (2009). Magnesium chloride in a polyethylene glycol formulation as a neuroprotective therapy for acute spinal cord injury: preclinical refinement and optimization. J Neurotrauma, 26(8):1379-93. https://doi.org/ 10.1089/neu.2009.0884.
42. 43. Kwon, B.K., Tetzlaff, W., Grauer, J.N., Beiner, J., & Vaccaro, A.R. (2004) Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J, 4:451-64. https://doi.org/10.1016/j.spinee.2003.07.007. 44. Landi, A. (2003). Update on tetraplegia. Journal of Hand Surgery, 28(3), 196-204. https://doi.org/10.1016/S0266-7681(02)00396-0.
43. 45. Lee, J.H., Roy, J., Sohn, H.M., Cheong, M., Liu, J., Stammers, A.T., Tetzlaff, W., & Kwon, B.K. (2010). Magnesium in a polyethylene glycol formulation provides neuroprotection after unilateral cervical spinal cord injury. Spine, 1;35(23):2041-8. https://doi.org/ 10.1097/BRS.0b013e3181d2d6c5.
44. 46. Martirosyan, N.L., Patel, A.A., Carotenuto, A., Kalani, M.Y., Bohl, M.A., & Preul, M.C. (2017). The role of therapeutic hypothermia in the management of acute spinal cord injury. Clin Neurol Neurosurg., 154:79-88. https://doi.org/10.1016/j.clineuro.2017.01.002.
45. 47. Nikulina, E., Tidwell, J.L., Dai, H.N., Bregman, B.S., Filbin, M.T. (2004). The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci U S A., 8;101(23):8786-90. https://doi.org/ 10.1073/pnas.0402595101.
46. 48. Ohbe, H., Koakutsu, T., & Kushimoto, S. (2019). Analysis of risk factors for hyponatremia in patients with acute spinal cord injury: a retrospective single-institution study in Japan. Spinal Cord, 57(3), 240-246. https://doi.org/10.1038/s41393-018-0208-6.
47. 49. O’Toole, J.E., Kaiser, M.G., Anderson, P.A., Arnold, P.M., Chi, J.H., Dhall, S. S., & et al. (2019). Congress of Neurological Surgeons systematic review and evidence-based guidelines on the evaluation and treatment of patients with thoracolumbar spine trauma: executive summary. Neurosurgery, 84:2–6. https://doi.org/10.1093/neuros/nyy394.
48. 50. Park, H.C., Shim, Y.S., & Ha, Y. (2005). Treatment of complete spinal cord injury patients by autologous bone marrow cell transplanta- tion and administration of granulocyte-macrophage colony stimulating factor. Tissue Eng 11(5–6):913-922. https://doi.org/10.1089/ten.2005.11.913.
49. 51. Popovich, P.G., Lemeshow, S., Gensel, J.C., & Tovar, C.A. (2012). Independent evaluation of the effects of glibenclamide on reducing progressive hemorrhagic necrosis af- ter cervical spinal cord injury. Exp Neurol, 233(2):615–22. https://doi.org/10.1016/j.expneurol.2010.11.016.
50. 52. Ryken, T.C., Hurlbert, R.J, Hadley, M.N., Aarabi, B., Dhall, S.S., & Gelb, D.E. (2013). The acute cardiopulmonary management of patients with cervical spinal cord injuries. Neurosurgery, 72 Suppl 2:84-92. https://doi.org/10.1227/neu.0b013e318276ee16.
51. 53. Sharp, K.G., Yee, K.M., Stiles ,T.L., Aguilar, R.M., & Steward, O. (2013). A re-assessment of the effects of treatment with a non-steroidal anti-inflammatory (ibuprofen) on promoting axon regeneration via RhoA inhibition after spinal cord injury. Exp Neurol., 248:321-37. https://doi.org/10.1016/j.expneurol.2013.06.023.
52. 54. Shi, Q., Gao, W., Han, X., Zhu, X., Sun, J., Xie, F., Hou, X., Yang, H., Dai, J., & Chen, L. (2014). Collagen scaffolds modified with collagen-binding bFGF promotes the neural regeneration in a rat hemisected spinal cord injury model. Sci China Life Sci., 57: 232–240. https://doi.org/10.1007/s11427-014-4612-7.
53. 55. Streijger, F., So, K., Manouchehri, N., Tigchelaar, S., Lee, J.H.T., & Okon, E.B. (2017). Changes in pressure, hemodynamics, and metabolism within the spinal cord during the first 7 days after injury using a porcine model. J Neurotrauma, 34(24):3336-3350. https://doi.org/ 10.1089/neu.2017.5034.
54. 56. Sultan, I., Lamba, N., Liew, A., Doung, P., Tewarie, I., Amamoo, J.J., Gannu, L., Chawla, S., Doucette, J., Cerecedo-Lopez, C.D., Papatheodorou, S., Tafel, I., Aglio, L.S., Smith, T.R., Zaidi, H., & Mekary, R.A. (2020). The safety and efficacy of steroid treatment for acute spinal cord injury. A Systematic Review and meta-analysis. Heliyon, 19;6(2):e03414. https://doi.org/ 10.1016/j.heliyon. 2020.e03414.
55. 57. Taylor, L., Jones, L., Tuszynski, M. H., & Blesch, A. (2006). Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord. Journal of Neuroscience, 26(38), 9713-9721. https://doi.org/10.1523/JNEUROSCI.0734-06.2006.
56. 58. Teasell, R. W., Mehta, S., Aubut, J. A. L., Foulon, B., Wolfe, D. L., Hsieh, J. T., ... & Spinal Cord Injury Rehabilitation Evidence Research Team. (2010). A systematic review of pharmacologic treatments of pain after spinal cord injury. Archives of physical medicine and rehabilitation, 91(5), 816-831. https:// doi.org/10.1016/j.apmr.2010.01.022.
57. 59. Temkin, N.R., Anderson, G.D., Winn, H.R., Ellenbogen, R.G., Britz, G.W., Schuster, J., Lucas, T., Newell, D.W., Mansfield, P.N., Machamer, J.E., Barber, J., & Dikmen, S.S. (2007). Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol, 6(1):29–38. https://doi.org/10.1016/S1474-4422(06)70630-5.
58. 60. Wells, J.E.A., Hurlbert, R.J., Fehlings, M.G., &Yong, V.W. (2003). Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain, 126:1628-37. https:// doi.org/10.1093/brain/awg178.
59. 61. Wyndaele, M., &Wyndaele, J.J. (2006) Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord, 44(9):523–9. https://doi.org/10.1038/sj.sc.3101893.
60. 62. Xing, B., Li, H., Wang, H., Mukhopadhyay, D., Fisher, D., Gilpin, C.J., & Li, S. (2011). RhoA-inhibiting NSAIDs promote axonal myelination after spinal cord injury. Exp Neurol., 231(2):247-60. https://doi.org/10.1016/j.expneurol.2011.06.018.
61. 63. Yılmaz, T., & Kaptanoğlu, E. (2015). Current and future medical therapeutic strategies for the functional repair of Spinal cord injury. World J Orthop, 18;6(1):42-55. https://doi.org/10.5312/wjo.v6.i1.42.
62. 64. Yoon, S.H., Shim, Y.S., & Park, Y.H. (2007). Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage- colony stimulating factor: Phase I/II clinical trial. Stem Cells 25(8):2066-2073. https://doi.org/10.1634/stemcells.2006-0807.
63. 65. Zhao, R.R., Andrews, M.R., Wang, D., Warren, P., Gullo, M., Schnell, L., Schwab, M.E., & Fawcett, J.W. (2013). Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. Eur J Neurosci., 38:2946-61. https://doi.org/10.1111/ejn.12276.
64. 66. Zörner, B., & Schwab, M. E. (2010). Anti‐Nogo on the go: From animal models to a clinical trial. Annals of the New York Academy of Sciences, 1198, E22-E34. https://doi.org/10.1111/j.1749-6632.2010.05566.x.