وقایع بیوشیمیایی و سلولی در آسیب‌های نخاعی: ازپاتوفیزیولوژی تا درمان

نوع مقاله : مقاله های پژوهشی

نویسنده

دکتری تخصصی ژنتیک مولکولی، مرکز تحقیقات ژنتیک انسانی، دانشگاه علوم پزشکی بقیه‌اله، تهران، ایران

چکیده

هنوز درمان قطعی برای آسیب‌های نخاعی که در اثر عوامل ترومایی (ناشی از حادثه) و غیر ترومایی (ناشی از بیماری‌ها) ایجاد می‌شوند، یافت نشده است و این امر به دلیل پاتوفیزیولوژی پیچیده‌ای است که این آسیب‌ها دارند؛ به ویژه اگر بیماری در مراحل مزمن باشد. این مسأله هزینه‌های اقتصادی و روانی گزافی را به خانواده و اجتماع تحمیل می‌نماید. از نظر بالینی، پاتوفیزیولوژی این بیماران به دو فاز اصلی آسیب اولیه و ثانویه تقسیم‌بندی می‌گردد. آسیب اولیه با ضایعه به نخاع شروع می‌شود و طی یک سری وقایع مولکولی ثانویه که به صورت آبشاری اتفاق می‌افتد، یک حفره‌ی بزرگ در ناحیه‌ی آسیب تشکیل می‌دهد و زخم گلیایی را ایجاد می‌کند که سد فیزیکی و شیمیایی در مقابل ترمیم نخاع آسیب‌دیده می‌باشد. به طور کلی، موانعی بر سر راه ترمیم نورون‌ها و درمان قطعی آسیب‌های نخاعی وجود دارد که استراتژی‌های ترمیمی مورد استفاده در درمان این بیماری باید بر این سدها غلبه کند. بسیاری از استراتژی‌های پیشنهادی، در مراحل آزمایشگاهی و پیش‌بالینی موفق بوده و حتی به مرحله‌ی بالینی نیز رسیده‌اند. پژوهش مروری حاضر، خلاصه‌ای از آخرین یافته‌های درمانی مؤثر در این بیماری را ارایه نمود.

کلیدواژه‌ها


عنوان مقاله [English]

Biochemical and Cellular Events in Spinal Cord Injury: From Pathophysiology to Treatment

نویسنده [English]

  • Houri Edalat
PhD in Molecular Genetics, Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
چکیده [English]

No definite treatment has been reported thus far for spinal cord injuries (SCI) that is mainly due to its complex nature and pathophysiology, specifically in chronic stages of the disease. The disease imposes lots of financial and psychological costs to the families and society. From pathophysiological aspects, the disease can be divided into two phases of primary and secondary injuries. The primary damage begins with an initial lesion which -during a series of secondary molecular events in the form of a cascade- produces a large cavity in the initial damaged area called glial scar. The glial scar creates a physical and chemical barrier against repairing the injured spinal cord. In fact, there are many barriers against recovery of neurons that regenerative treatment strategies have to overcome. Many of methods suggested to cure SCI have been shown to be successful in vitro and pre-clinical studies, and have not reached clinical trial phases. This review study provides some of the latest strategies shown to be effective for treatment of SCI.

  1. Myers J. Spinal cord injury and male infertility-a review of current literature, knowledge gaps, and future research. Transl Androl Urol 2018; 7(Suppl 3): S373-S382.
  2. Qi Z, Middleton JW, Malcolm A. Bowel dysfunction in spinal cord injury. Curr Gastroenterol Rep 2018; 20(10): 47.
  3. Sweis R, Biller J. Systemic complications of spinal cord injury. Curr Neurol Neurosci Rep 2017; 17(2): 8.
  4. Festoff BW. Designing drugs that encourage spinal cord injury healing. Expert Opin Drug Discov 2014; 9(10): 1151-65.
  5. Karsy M, Hawryluk G. Pharmacologic management of acute spinal cord injury. Neurosurg Clin N Am 2017; 28(1): 49-62.
  6. Chen X, Liu X, Li B, Zhang Q, Wang J, Zhang W, et al. Cold inducible RNA binding protein is involved in chronic hypoxia induced neuron apoptosis by down-regulating HIF-1alpha expression and regulated By microRNA-23a. Int J Biol Sci 2017; 13(4): 518-31.
  7. Mousavi SA, Kooshki M, Mehrabi Kooshki A. Physical and mental illness in capable in compare to disable veterans with spinal cord injury. J Isfahan Med Sch 2011; 29(145): 831-9. [In Persian].
  8. Mekki M, Delgado AD, Fry A, Putrino D, Huang V. Robotic rehabilitation and spinal cord injury: A narrative review. Neurotherapeutics 2018; 15(3): 604-17.
  9. Ghorbani Alvanegh A, Tavallaei M, Edalat H. Evaluating the epigenetic effects of the miR17/92 cluster in noninvasive screening of genetically-based respiratory diseases. J Mil Med 2018; 20(1): 116-26. [In Persian].
  10. Alvanegh AG, Edalat H, Fallah P, Tavallaei M. Decreased expression of miR-20a and miR-92a in the serum from sulfur mustard-exposed patients during the chronic phase of resulting illness. Inhal Toxicol 2015; 27(13): 682-8.
  11. Ansari MH, Irani S, Edalat H, Amin R, Mohammadi RA. Deregulation of miR-93 and miR-143 in human esophageal cancer. Tumour Biol 2016; 37(3): 3097-103.
  12. Edalat H, Hajebrahimi Z, Movahedin M, Tavallaei M, Amiri S, Mowla SJ. p75NTR suppression in rat bone marrow stromal stem cells significantly reduced their rate of apoptosis during neural differentiation. Neurosci Lett 2011; 498(1): 15-9.
  13. Edalat H, Hajebrahimi Z, Pirhajati V, Tavallaei M, Movahedin M, Mowla SJ. Exogenous expression of Nt-3 and TrkC genes in bone marrow stromal cells elevated the survival rate of the cells in the course of neural differentiation. Cell Mol Neurobiol 2017; 37(7): 1187-94.
  14. Edalat H, Sadeghizadeh M, Jamali Zavarehei M. Codon 12 K-ras mutation detection in Iranian patients with colorectal cancer using PCR-RFLP method. Modares J Med Sci 2010; 9(2): 33-8. [In Persian].
  15. Ghorbani Alvanegh A, Tavallaei M, Edalat H. Severe decline in Mir-20a and Mir-92a in the context of the Mir-17-92 cluster: Ideal biomarkers of various COPD subtypes. Acta Med Iran 2019; 57(1):17-26.
  16. Christopher and Dana Reeve Foundation. One degree of separation: paralysis and spinal cord injury in the united states. Short Hills, NJ: Christopher and Dana Reeve Foundation; 2009.
  17. Farry A, Baxter D. The incidence and prevalence of spinal cord injury in canada: overview and estimates based on current evidence. Vancouver, BC, Canada: Rick Hansen Institute; 2011.
  18. Wyndaele M, Wyndaele JJ. Incidence, prevalence and epidemiology of spinal cord injury: what learns a worldwide literature survey? Spinal Cord 2006; 44(9): 523-9.
  19. Volarevic V, Erceg S, Bhattacharya SS, Stojkovic P, Horner P, Stojkovic M. Stem cell-based therapy for spinal cord injury. Cell Transplant 2013; 22(8): 1309-23.
  20. Chhabra HS, Sarda K. Clinical translation of stem cell based interventions for spinal cord injury - Are we there yet? Adv Drug Deliv Rev 2017; 120: 41-9.
  21. Cho N, Hachem LD, Fehlings MG. Spinal cord edema after spinal cord injury: From pathogenesis to management. In: Badaut J, Plesnila N, editors. Brain Edema. San Diego, CA: Academic Press; 2017. p. 261-75.
  22. Badhiwala JH, Ahuja CS, Fehlings MG. Time is spine: A review of translational advances in spinal cord injury. J Neurosurg Spine 2018; 30(1): 1-18.
  23. Quadri SA, Farooqui M, Ikram A, Zafar A, Khan MA, Suriya SS, et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg Rev 2018.
  24. Oyinbo CA. Secondary injury mechanisms in traumatic spinal cord injury: A nugget of this multiply cascade. Acta Neurobiol Exp (Wars) 2011; 71(2): 281-99.
  25. Okada S. The pathophysiological role of acute inflammation after spinal cord injury. Inflammation and Regeneration 2016; 36(1): 20.
  26. Anwar MA, Al Shehabi TS, Eid AH. Inflammogenesis of secondary spinal cord injury. Front Cell Neurosci 2016; 10: 98.
  27. McIntyre A, Benton B, Janzen S, Iruthayarajah J, Wiener J, Eng JJ, et al. A mapping review of randomized controlled trials in the spinal cord injury research literature. Spinal Cord 2018; 56(8): 725-32.
  28. Dalamagkas K, Tsintou M, Seifalian A, Seifalian AM. translational regenerative therapies for chronic spinal cord injury. Int J Mol Sci 2018; 19(6).
  29. Ahuja CS, Nori S, Tetreault L, Wilson J, Kwon B, Harrop J, et al. Traumatic spinal cord injury-repair and regeneration. Neurosurgery 2017; 80(3S): S9-S22.
  30. Ahuja CS, Martin AR, Fehlings M. Recent advances in managing a spinal cord injury secondary to trauma. F1000Res 2016; 5.
  31. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 2006; 7(8): 617-27.
  32. Rosenberg LJ, Teng YD, Wrathall JR. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion. J Neurosci 1999; 19(1): 464-75.
  33. Hulsebosch CE, Hains BC, Waldrep K, Young W. Bridging the gap: From discovery to clinical trials in spinal cord injury. J Neurotrauma 2000; 17(12): 1117-28.
  34. Lu J, Ashwell K. Olfactory ensheathing cells: Their potential use for repairing the injured spinal cord. Spine (Phila Pa 1976) 2002; 27(8): 887-92.
  35. Xu XM, Chen A, Guenard V, Kleitman N, Bunge MB. Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J Neurocytol 1997; 26(1): 1-16.
  36. Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 2002; 416(6881): 636-40.
  37. Zorner B, Schwab ME. Anti-Nogo on the go: from animal models to a clinical trial. Ann N Y Acad Sci 2010; 1198(Suppl 1): E22-E34.
  38. McGraw J, Hiebert GW, Steeves JD. Modulating astrogliosis after neurotrauma. J Neurosci Res 2001; 63(2): 109-15.
  39. Ramer MS, Priestley JV, McMahon SB. Functional regeneration of sensory axons into the adult spinal cord. Nature 2000; 403(6767): 312-6.
  40. Benowitz LI, Goldberg DE, Madsen JR, Soni D, Irwin N. Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proc Natl Acad Sci USA 1999; 96(23): 13486-90.
  41. Hulsebosch CE. Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 2002; 26(1-4): 238-55.
  42. Zompa EA, Cain LD, Everhart AW, Moyer MP, Hulsebosch CE. Transplant therapy: Recovery of function after spinal cord Injury. J Neurotrauma 1997; 14(8): 479-506.
  43. Sarda K, Chhabra HS. CellularTransplantation for human spinal cord injury: An overview. In: Chhabra HS, editor. Textbook on comprehensive management of spinal cord. New Delhi, India: Wolters Kluwer; 2015. p. 1048-58.
  44. Grill R, Murai K, Blesch A, Gage FH, Tuszynski MH. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J Neurosci 1997; 17(14): 5560-72.
  45. Murray M, Fischer I. Transplantation and gene therapy: combined approaches for repair of spinal cord injury. Neuroscientist 2001; 7(1): 28-41.
  46. Lammertse DP, Jones LA, Charlifue SB, Kirshblum SC, Apple DF, Ragnarsson KT, et al. Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal Cord 2012; 50(9): 661-71.
  47. Falci S, Holtz A, Akesson E, Azizi M, Ertzgaard P, Hultling C, et al. Obliteration of a posttraumatic spinal cord cyst with solid human embryonic spinal cord grafts: first clinical attempt. J Neurotrauma 1997; 14(11): 875-84.
  48. Thompson FJ, Reier PJ, Uthman B, Mott S, Fessler RG, Behrman A, et al. Neurophysiological assessment of the feasibility and safety of neural tissue transplantation in patients with syringomyelia. J Neurotrauma 2001; 18(9): 931-45.
  49. Johnson PJ, Tatara A, McCreedy DA, Shiu A, Sakiyama-Elbert SE. Tissue-engineered fibrin scaffolds containing neural progenitors enhance functional recovery in a subacute model of SCI. Soft Matter 2010; 6(20): 5127-37.
  50. Hollis ER. Axon guidance molecules and neural circuit remodeling after spinal cord injury. Neurotherapeutics 2016; 13(2): 360-9.
  51. Aasdi A, Erfanian Omidvar A. Restoring the stepping-like movement in spinal rat by electrical micro-stimulation of motor primitive blocks. J Isfahan Med Sch 2013; 31(250): 1324-8. [In Persian].
  52. Liu NK, Xu XM. Neuroprotection and its molecular mechanism following spinal cord injury. Neural Regen Res 2012; 7(26): 2051-62.
  53. Cheriyan T, Ryan DJ, Weinreb JH, Cheriyan J, Paul JC, Lafage V, et al. Spinal cord injury models: A review. Spinal Cord 2014; 52(8): 588-95.
  54. Edalat H. Cell therapy and gene therapy in spinal cord injuries. J Isfahan Med Sch 2019; 36(501): 1297-307. [In Persian].
  55. Ahuja CS, Fehlings M. Concise review: bridging the gap: Novel neuroregenerative and neuroprotective strategies in spinal cord injury. Stem Cells Transl Med 2016; 5(7): 914-24.