The fate of neurons after traumatic spinal cord injury in rats: A systematic review

Document Type: Review Article


1 Pediatric Urology and Regenerative Medicine Research Center, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran

2 Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Chemical and Biomolecular Engineering, University of Melbourne, Victoria 3010, Australia

4 Brain and Mind Center, University of Sydney, 94 Mallett St, Camperdown NSW 2050, Australia

5 Cochrane Schizophrenia Group, Institute of Mental Health, University of Nottingham, Nottingham, UK

6 Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive, CA 90095, USA


Objective(s): To reach an evidence-based knowledge in the context of the temporal-spatial pattern of neuronal death and find appropriate time of intervention in order to preserve spared neurons and promote regeneration after traumatic spinal cord injury (TSCI).
Materials and Methods: The study design was based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-guided systematic review. PubMed and EMBASE were searched (24 October, 2015) with no temporal or linguistic restrictions. Hand-search was performed in the bibliographies of relevant articles. Non-interventional animal studies evaluating time-dependent neuronal death following acute mechanical trauma to the spinal cord were included. We separately evaluated the fate of various populations of neurons including propriospinal neurons, ventral motor neurons, Clarke’s column neurons, and supraspinal neurons.
Results: We found 11,557 non-duplicated studies. Screening through the titles and abstracts led to 549 articles, 49 of which met the inclusion criteria. Both necrotic and apoptotic neuronal deaths occur after TSCI, though necrosis is the prominent mechanism. There are differences in the responses of intrinsic neurons of the spinal cord to the TSCI. Also, the extent of neuronal death in the supraspinal neurons depends on the anatomical location of their axons.
Conclusion: In order to develop new therapies, selection of the injury model and time of intervention has a crucial role in the efficacy of therapy. In addition, examining the safety and efficacy of an intervention by reliable methods not confounded by the injury-related changes would promote translation of therapies to the clinical application.


Main Subjects

1. Saadat S, Javadi M, Divshali BS, Tavakoli AH, Ghodsi SM, Montazeri A, et al. Health-related quality of life among individuals with long-standing spinal cord injury: a comparative study of veterans and non-veterans. BMC Public Health 2010; 10:1-7.
2. Eslami V, Saadat S, Habibi Arejan R, Vaccaro AR, Ghodsi SM, Rahimi-Movaghar V. Health-related quality of life among individuals with long-standing spinal cord injury. Spinal Cord 2012; 50:899-903.
3. Rahimi-Movaghar V, Moradi-Lakeh M, Rasouli MR, Vaccaro AR. Burden of spinal cord injury in Tehran, Iran. Spinal Cord 2010; 48:492-497.
4. Kim ES, Kim GM, Lu X, Hsu CY, Xu XM. Neural circuitry of the adult rat central nervous system after spinal cord injury: a study using fast blue and the Bartha strain of pseudorabies virus. J Neurotrauma 2002; 19:787-800.
5. Naso WB, Cox RD, McBryde JP, Perot PL Jr. Rubrospinal neurons and retrograde transport of fluoro-gold in acute spinal cord injury--a dose-response curve. Neurosci Lett 1993; 155:125-127.
6. Feringa ER, Vahlsing HL. Labeled corticospinal neurons one year after spinal cord transection. Neurosci lett 1985; 58:283-286.
7. Nielson JL, Sears-Kraxberger I, Strong MK, Wong JK, Willenberg R, Steward O. Unexpected survival of neurons of origin of the pyramidal tract after spinal cord injury. J Neurosci 2010; 30:11516-11528.
8. Beattie MS, Farooqui AA, Bresnahan JC. Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma 2000; 17:915-925.
9. Chu D, Qiu J, Grafe M, Fabian R, Kent TA, Rassin D, et al. Delayed cell death signaling in traumatized central nervous system: hypoxia. Neurochem Res 2002; 27:97-106.
10. Cheriyan T, Ryan DJ, Weinreb JH, Cheriyan J, Paul JC, Lafage V, et al. Spinal cord injury models: a review. Spinal Cord 2014; 52:588-595.
11. Sharif-Alhoseini M, Khormali M, Rezaei M, Safdarian M, Hajighadery A, Khalatbari MM, et al. Animal models of spinal cord injury: a systematic review. Spinal Cord 2017; 55:714-721.
12. Metz GA, Curt A, van de Meent H, Klusman I, Schwab ME, Dietz V. Validation of the weight-drop contusion model in rats: a comparative study of human spinal cord injury. J Neurotrauma 2000; 17:1-17.
13. Hassannejad Z, Sharif-Alhoseini M, Shakouri-Motlagh A, Vahedi F, Zadegan SA, Mokhatab M, et al. Potential variables affecting the quality of animal studies regarding pathophysiology of traumatic spinal cord injuries. Spinal Cord 2016; 54: 579-583.
14. Andrade M, Hanania F, Daci K, Leme R, Chadi G. Contuse lesion of the rat spinal cord of moderate intensity leads to a higher time-dependent secondary neurodegeneration than severe one: An open-window for experimental neuroprotective interventions. Tissue Cell 2008; 40:143-156.
15. Bose P, Parmer R, Reier PJ, Thompson FJ. Morphological changes of the soleus motoneuron pool in chronic midthoracic contused rats. Exp Neurol 2005; 191:13-23.
16. Conta AC, Stelzner DJ. Differential vulnerability of propriospinal tract neurons to spinal cord contusion injury. J Comp Neurol 2004; 479:347-359.
17. Eidelberg E, Nguyen LH, Polich R, Walden JG. Transsynaptic degeneration of motoneurones caudal to spinal cord lesions. Brain Res Bull 1989; 22:39-45.
18. Feringa ER, Gilbertie WJ, Vahlsing HL. Histologic evidence for death of cortical neurons after spinal cord transection. Neurology 1984; 34:1002-1006.
19. Grossman S, Rosenberg L, Wrathall J. Temporal–spatial pattern of acute neuronal and glial loss after spinal cord contusion. Exp Neurol 2001; 168:273-282.
20. Grossman SD, Wolfe BB, Yasuda RP, Wrathall JR. Changes in NMDA receptor subunit expression in response to contusive spinal cord injury. J Neurochem 2000; 75:174-184.
21. Holtz A, Nyström B, Gerdin B, Olsson Y. Neuropathological changes and neurological function after spinal cord compression in the rat. J Neurotrauma 1990; 7:155-167.
22. James ND, Bartus K, Grist J, Bennett DL, McMahon SB, Bradbury EJ. Conduction failure following spinal cord injury: functional and anatomical changes from acute to chronic stages. J Neurosci 2011; 31:18543-18555.
23. Liu PH, Wang YJ, Tseng GF. Close axonal injury of rubrospinal neurons induced transient perineuronal astrocytic and microglial reaction that coincided with their massive degeneration. Exp Neurol 2003; 179:111-126.
24. Liu XZ, Xu XM, Hu R, Du C, Zhang SX, McDonald JW, et al. Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 1997; 17:5395-5406.
25. Lou J, Lenke LG, Ludwig FJ, O’Brien MF. Apoptosis as a mechanism of neuronal cell death following acute experimental spinal cord injury. Spinal Cord 1998; 36:683-690.
26. McBride RL, Feringa ER, Garver MK, Williams JJ. Retrograde transport of fluoro-gold in corticospinal and rubrospinal neurons 10 and 20 weeks after T-9 spinal cord transection. Exp Neurol 1990; 108:83-85.
27. Morino T, Ogata T, Horiuchi H, Takeba J, Okumura H, Miyazaki T, et al. Delayed neuronal damage related to microglia proliferation after mild spinal cord compression injury. Neurosci Res 2003; 46:309-318.
28. Qiu J, Nesic O, Ye Z, Rea H, Westlund KN, Xu GY, et al. Bcl-xL expression after contusion to the rat spinal cord. J Neurotrauma 2001; 18:1267-1278.
29. Rosenberg LJ, Wrathall JR. Quantitative analysis of acute axonal pathology in experimental spinal cord contusion. J Neurotrauma 1997; 14:823-838.
30. Siebert JR, Middleton FA, Stelzner DJ. Long descending cervical propriospinal neurons differ from thoracic propriospinal neurons in response to low thoracic spinal injury. BMC Neurosci 2010; 11:148-165.
31. Springer JE, Azbill RD, Knapp PE. Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat Med 1999; 5:943-946.
32. Steencken AC, Smirnov I, Stelzner DJ. Cell survival or cell death: differential vulnerability of long descending and thoracic propriospinal neurons to low thoracic axotomy in the adult rat. Neuroscience 2011; 194:359-371.
33. Wang Y-J, HO H-W, TSENG G-F. Fate of the supraspinal collaterals of cord-projection neurons following upper spinal axonal injury. J Neurotrauma 2000; 17:231-241.
34. Wang Z, Zhang C, Hong Z, Chen H, Chen W, Chen G. C/EBP homologous protein (CHOP) mediates neuronal apoptosis in rats with spinal cord injury. Exp Ther Med 2013; 5:107-111.
35. Yick LW, Wu W, So KF, Wong S-Y. Time course of NOS expression and neuronal death in Clarke’s nucleus following traumatic injury in adult rat spinal cord. Neurosci Lett 1998; 241:156-158.
36. Barron KD, Dentinger MP, Popp AJ, Mankes R. Neurons of layer Vb of rat sensorimotor cortex atrophy but do not die after thoracic cord transection. J Neuropathol Exp Neurol 1988; 47:62-74.
37. Choo AM, Liu J, Dvorak M, Tetzlaff W, Oxland TR. Secondary pathology following contusion, dislocation, and distraction spinal cord injuries. Exp Neurol 2008; 212:490-506.
38. Ek CJ, Habgood MD, Callaway JK, Dennis R, Dziegielewska KM, Johansson PA, et al. Spatio-temporal progression of grey and white matter damage following contusion injury in rat spinal cord. PLoS One 2010; 5:12021-12036.
39. Fehlings MG, Tator CH. The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury. Exp Neurol 1995; 132:220-228.
40. Feringa ER, Lee GW, Vahlsing HL. Cell death in Clarke’s column after spinal cord transection. J Neuropathol Exp Neurol 1985; 44:156-164.
41. Feringa ER, McBride RL, Pruitt JN. Loss of neurons in the red nucleus after spinal cord transection. Exp Neurol 1988; 100:112-120.
42. Feringa ER, Pruitt JN, 2nd, McBride RL, Vahlsing HL. Changes in number and size of Clarke’s column neurons after cord transection. J Neuropathol Exp Neurol 1987; 46:695-702.
43. Feringa ER, Vahlsing HL, Smith BE. Retrograde transport in corticospinal neurons after spinal cord transection. Neurology 1983; 33:478-482.
44. Hains BC, Black JA, Waxman SG. Primary cortical motor neurons undergo apoptosis after axotomizing spinal cord injury. J Comp Neurol 2003; 462:328-341.
45. Huang WL, George KJ, Ibba V, Liu MC, Averill S, Quartu M, et al. The characteristics of neuronal injury in a static compression model of spinal cord injury in adult rats. Eur J Neurosci 2007; 25:362-372.
46. Lee BH, Lee KH, Kim UJ, Yoon DH, Sohn JH, Choi SS, et al. Injury in the spinal cord may produce cell death in the brain. Brain Res 2004; 1020:37-44.
47.McBride RL, Feringa ER. Ventral horn motoneurons 10, 20 and 52 weeks after T-9 spinal cord transection. Brain Res Bull 1992; 28:57-60.
48. McBride RL, Feringa ER, Garver MK, Williams JK, Jr. Prelabeled red nucleus and sensorimotor cortex neurons of the rat survive 10 and 20 weeks after spinal cord transection. J Neuropathol Exp Neurol 1989; 48:568-576.
49. McBride RL, Feringa ER, Smith BE. The fate of prelabeled Clarke’s column neurons after axotomy. Exp Neurol 1988; 102:236-243.
50. Prendergast J, Stelzner DJ. Changes in the magnocellular portion of the red nucleus following thoracic hemisection in the neonatal and adult rat. J Comp Neurol 1976; 166:163-171.
51. Siebert JR, Middelton FA, Stelzner DJ. Intrinsic response of thoracic propriospinal neurons to axotomy. BMC Neurosci 2010; 11:69-92.
52. Steencken AC, Stelzner D. Loss of propriospinal neurons after spinal contusion injury as assessed by retrograde labeling. Neuroscience 2010; 170:971-980.
53. Theriault E, Tator CH. Persistence of rubrospinal projections following spinal cord injury in the rat. J Comp Neurol 1994; 342:249-258.
54. Wang YJ, Chen JR, Tseng GF. Fate of the soma and dendrites of cord-projection central neurons after proximal and distal spinal axotomy: an intracellular dye injection study. J Neurotrauma 2002; 19:1487-1502.
55. Yong C, Arnold PM, Zoubine MN, Citron BA, Watanabe I, Berman NE, et al. Apoptosis in cellular compartments of rat spinal cord after severe contusion injury. J Neurotrauma 1998; 15:459-472.
56. Dusart I, Schwab M. Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur J Neurosci 1994; 6:712-724.
57. Li GL, Brodin G, Farooque M, Funa K, Holtz A, Wang WL, et al. Apoptosis and expression of Bcl-2 after compression trauma to rat spinal cord. J Neuropathol Exp Neurol 1996; 55:280-289.
58. Houle JD, Ye JH. Survival of chronically-injured neurons can be prolonged by treatment with neurotrophic factors. Neuroscience 1999; 94:929-936.
59. Wang L, Hu B, Wong WM, Lu P, Wu W, Xu XM. Glial and axonal responses in areas of Wallerian degeneration of the corticospinal and dorsal ascending tracts after spinal cord dorsal funiculotomy. Neuropathology 2009; 29:230-241.
60. Sun S, Li F, Gao X, Zhu Y, Chen J, Zhu X, et al. Calbindin-D28K inhibits apoptosis in dopaminergic neurons by activation of the PI3-kinase-Akt signaling pathway. Neuroscience 2011; 199:359-367.
61. Brook GA, Plate D, Franzen R, Martin D, Moonen G, Schoenen J, et al. Spontaneous longitudinally orientated axonal regeneration is associated with the Schwann cell framework within the lesion site following spinal cord compression injury of the rat. J Neurosci Res 1998; 53:51-65.
62. Nashmi R, Fehlings MG. Changes in axonal physiology and morphology after chronic compressive injury of the rat thoracic spinal cord. Neuroscience 2001; 104:235-251.
63. Frei E, Klusman I, Schnell L, Schwab ME. Reactions of oligodendrocytes to spinal cord injury: cell survival and myelin repair. Exp Neurol 2000; 163:373-380.
64. LaPlaca MC, Simon CM, Prado GR, Cullen DK. CNS injury biomechanics and experimental models. Prog Brain Res 2007; 161:13-26.
65. Artal-Sanz M, Tavernarakis N. Proteolytic mechanisms in necrotic cell death and neurodegeneration. FEBS letters 2005; 579:3287-3296.
66. Barres BA, Barde Y. Neuronal and glial cell biology. Curr opin neurobiol 2000; 10:642-648.
67. Frade JM, Ovejero-Benito MC. Neuronal cell cycle: the neuron itself and its circumstances. Cell Cycle 2015; 14:712-720.
68. Wang Y, Wang W, Li Z, Hao S, Wang B. A novel perspective on neuron study: damaging and promoting effects in different neurons induced by mechanical stress. Biomech Model Mechanobiol 2016; 15:1019–1027.
69. Lu J, Ashwell KW, Waite P. Advances in secondary spinal cord injury: role of apoptosis. Spine (Phila Pa 1976) 2000; 25:1859-1866.
70. Allen RT, Hunter WJ, 3rd, Agrawal DK. Morphological and biochemical characterization and analysis of apoptosis. J Pharmacol Toxicol Methods 1997; 37:215-228.
71. Willingham MC. Cytochemical methods for the detection of apoptosis. J Histochem Cytochem 1999; 47:1101-1110.