Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Spinal cord repair strategies: why do they work?

Abstract

There are now numerous preclinical reports of various experimental treatments promoting some functional recovery after spinal cord injury. Surprisingly, perhaps, the mechanisms that underlie recovery have rarely been definitively established. Here, we critically evaluate the evidence that regeneration of damaged pathways or compensatory collateral sprouting can promote recovery. We also discuss several more speculative mechanisms that might putatively explain or confound some of the reported outcomes of experimental interventions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Structure of the spinal cord.
Figure 2: The major functional deficits associated with spinal cord injury arise from the interruption of long ascending and descending spinal tracts.
Figure 3: Restoration of function after spinal cord injury might arise from anatomical plasticity of damaged or spared connections.
Figure 4: Various well-established phenomena might contribute to functional recovery from spinal cord injury after experimental interventions.

References

  1. Schwab, M. E. & Bartholdi, D. Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370 (1996).

    CAS  PubMed  Google Scholar 

  2. Becerra, J. L. et al. MR-pathologic comparisons of wallerian degeneration in spinal cord injury. AJNR Am. J. Neuroradiol. 16, 125–133 (1995).

    CAS  PubMed  Google Scholar 

  3. Bregman, B. S. et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501 (1995).

    CAS  PubMed  Google Scholar 

  4. GrandPre, T., Li, S. & Strittmatter, S. M. Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551 (2002).

    CAS  PubMed  Google Scholar 

  5. Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).

    CAS  PubMed  Google Scholar 

  6. Yick, L. W., Cheung, P. T., So, K. F. & Wu, W. Axonal regeneration of Clarke's neurons beyond the spinal cord injury scar after treatment with chondroitinase ABC. Exp. Neurol. 182, 160–168 (2003).

    CAS  PubMed  Google Scholar 

  7. Bradbury, E. J. et al. NT-3 promotes growth of lesioned adult rat sensory axons ascending in the dorsal columns of the spinal cord. Eur. J. Neurosci. 11, 3873–3883 (1999).

    CAS  PubMed  Google Scholar 

  8. Grill, R., Murai, K., Blesch, A., Gage, F. H. & Tuszynski, M. H. Cellular delivery of neurotrophin-3 promotes corticospinal axonal growth and partial functional recovery after spinal cord injury. J. Neurosci. 17, 5560–5572 (1997).

    CAS  PubMed  Google Scholar 

  9. Oudega, M. & Hagg, T. Nerve growth factor promotes regeneration of sensory axons into adult rat spinal cord. Exp. Neurol. 140, 218–229 (1996).

    CAS  PubMed  Google Scholar 

  10. Neumann, S. & Woolf, C. J. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83–91 (1999).

    CAS  PubMed  Google Scholar 

  11. Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).

    CAS  PubMed  Google Scholar 

  12. Liu, Y. et al. Transplants of fibroblasts genetically modified to express BDNF promote regeneration of adult rat rubrospinal axons and recovery of forelimb function. J. Neurosci. 19, 4370–4387 (1999).

    CAS  PubMed  Google Scholar 

  13. Bunge, M. B. Transplantation of purified populations of Schwann cells into lesioned adult rat spinal cord. J. Neurol. 242, S36–S39 (1994).

    CAS  PubMed  Google Scholar 

  14. Li, Y., Field, P. M. & Raisman, G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000–2002 (1997).

    CAS  PubMed  Google Scholar 

  15. Lu, P., Jones, L. L., Snyder, E. Y. & Tuszynski, M. H. Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp. Neurol. 181, 115–129 (2003).

    CAS  PubMed  Google Scholar 

  16. Kim, D. et al. Transplantation of genetically modified fibroblasts expressing BDNF in adult rats with a subtotal hemisection improves specific motor and sensory functions. Neurorehabil. Neural Repair 15, 141–150 (2001).

    CAS  PubMed  Google Scholar 

  17. Li, Y., Field, P. M. & Raisman, G. Regeneration of adult rat corticospinal axons induced by transplanted olfactory ensheathing cells. J. Neurosci. 18, 10514–10524 (1998).

    CAS  PubMed  Google Scholar 

  18. Wall, P. D. The sensory and motor role of impulses travelling in the dorsal columns towards cerebral cortex. Brain 93, 505–524 (1970).

    CAS  PubMed  Google Scholar 

  19. Windle, W. F., Smart, J. O. & Beers, J. J. Residual function after subtotal spinal cord transection in adult cats. Neurology 8, 518–521 (1958).

    CAS  PubMed  Google Scholar 

  20. Nathan, P. W. Effects on movement of surgical incisions into the human spinal cord. Brain 117, 337–346 (1994).

    PubMed  Google Scholar 

  21. Ramer, M. S., Priestley, J. V. & McMahon, S. B. Functional regeneration of sensory axons into the adult spinal cord. Nature 403, 312–316 (2000).

    CAS  PubMed  Google Scholar 

  22. Steinmetz, M. P. et al. Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through the dorsal root entry zone in the mammalian spinal cord. J. Neurosci. 25, 8066–8076 (2005).

    CAS  PubMed  Google Scholar 

  23. Li, S. et al. Blockade of Nogo-66, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein by soluble Nogo-66 receptor promotes axonal sprouting and recovery after spinal injury. J. Neurosci. 24, 10511–10520 (2004).

    CAS  PubMed  Google Scholar 

  24. Mitsui, T., Shumsky, J. S., Lepore, A. C., Murray, M. & Fischer, I. Transplantation of neuronal and glial restricted precursors into contused spinal cord improves bladder and motor functions, decreases thermal hypersensitivity, and modifies intraspinal circuitry. J. Neurosci. 25, 9624–9636 (2005).

    CAS  PubMed  Google Scholar 

  25. Wong, L. F. et al. Retinoic acid receptor β2 promotes functional regeneration of sensory axons in the spinal cord. Nature Neurosci. 9, 243–250 (2006).

    CAS  PubMed  Google Scholar 

  26. Little, J. W., Harris, R. M. & Sohlberg, R. C. Locomotor recovery following subtotal spinal cord lesions in a rat model. Neurosci. Lett. 87, 189–194 (1988).

    CAS  PubMed  Google Scholar 

  27. Little, J. W., Ditunno, J. F. Jr, Stiens, S. A. & Harris, R. M. Incomplete spinal cord injury: neuronal mechanisms of motor recovery and hyperreflexia. Arch. Phys. Med. Rehabil. 80, 587–599 (1999).

    CAS  PubMed  Google Scholar 

  28. Burns, S. P., Golding, D. G., Rolle, W. A. Jr, Graziani, V. & Ditunno, J. F. Jr. Recovery of ambulation in motor-incomplete tetraplegia. Arch. Phys. Med. Rehabil. 78, 1169–1172 (1997).

    CAS  PubMed  Google Scholar 

  29. Raineteau, O. & Schwab, M. E. Plasticity of motor systems after incomplete spinal cord injury. Nature Rev. Neurosci. 2, 263–273 (2001).

    CAS  Google Scholar 

  30. Smith, P. M. & Jeffery, N. D. Spinal shock — comparative aspects and clinical relevance. J. Vet. Intern. Med. 19, 788–793 (2005).

    CAS  PubMed  Google Scholar 

  31. Alstermark, B., Lundberg, A., Pettersson, L. G., Tantisira, B. & Walkowska, M. Motor recovery after serial spinal cord lesions of defined descending pathways in cats. Neurosci. Res. 5, 68–73 (1987).

    CAS  PubMed  Google Scholar 

  32. McKenna, J. E. & Whishaw, I. Q. Complete compensation in skilled reaching success with associated impairments in limb synergies, after dorsal column lesion in the rat. J. Neurosci. 19, 1885–1894 (1999).

    CAS  PubMed  Google Scholar 

  33. Weidner, N., Ner, A., Salimi, N. & Tuszynski, M. H. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc. Natl Acad. Sci. USA 98, 3513–3518 (2001).

    CAS  PubMed  Google Scholar 

  34. Bareyre, F. M., Kerschensteiner, M., Misgeld, T. & Sanes, J. R. Transgenic labeling of the corticospinal tract for monitoring axonal responses to spinal cord injury. Nature Med. 11, 1355–1360 (2005).

    CAS  PubMed  Google Scholar 

  35. Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nature Neurosci. 7, 269–277 (2004).

    CAS  PubMed  Google Scholar 

  36. Thallmair, M. et al. Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nature Neurosci. 1, 124–131 (1998).

    CAS  PubMed  Google Scholar 

  37. Z'Graggen, W. J. et al. Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats. J. Neurosci. 18, 4744–4757 (1998).

    CAS  PubMed  Google Scholar 

  38. Raineteau, O., Fouad, K., Noth, P., Thallmair, M. & Schwab, M. E. Functional switch between motor tracts in the presence of the mAb IN-1 in the adult rat. Proc. Natl Acad. Sci. USA 98, 6929–6934 (2001).

    CAS  PubMed  Google Scholar 

  39. Raineteau, O., Fouad, K., Bareyre, F. M. & Schwab, M. E. Reorganization of descending motor tracts in the rat spinal cord. Eur. J. Neurosci. 16, 1761–1771 (2002).

    PubMed  Google Scholar 

  40. Li, S. & Strittmatter, S. M. Delayed systemic Nogo-66 receptor antagonist promotes recovery from spinal cord injury. J. Neurosci. 23, 4219–4227 (2003).

    CAS  PubMed  Google Scholar 

  41. Li, S., Kim, J. E., Budel, S., Hampton, T. G. & Strittmatter, S. M. Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury. Mol. Cell. Neurosci. 29, 26–39 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee, J. K., Kim, J. E., Sivula, M. & Strittmatter, S. M. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci. 24, 6209–6217 (2004).

    CAS  PubMed  Google Scholar 

  43. Markus, T. M. et al. Recovery and brain reorganization after stroke in adult and aged rats. Ann. Neurol. 58, 950–953 (2005).

    PubMed  Google Scholar 

  44. Carulli, D., Laabs, T., Geller, H. M. & Fawcett, J. W. Chondroitin sulfate proteoglycans in neural development and regeneration. Curr. Opin. Neurobiol. 15, 116–120 (2005).

    PubMed  Google Scholar 

  45. Rhodes, K. E. & Fawcett, J. W. Chondroitin sulphate proteoglycans: preventing plasticity or protecting the CNS? J. Anat. 204, 33–48 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Celio, M. R., Spreafico, R., De, B. S. & Vitellaro-Zuccarello, L. Perineuronal nets: past and present. Trends Neurosci. 21, 510–515 (1998).

    CAS  PubMed  Google Scholar 

  47. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002).

    CAS  PubMed  Google Scholar 

  48. Corvetti, L. & Rossi, F. Degradation of chondroitin sulfate proteoglycans induces sprouting of intact purkinje axons in the cerebellum of the adult rat. J. Neurosci. 25, 7150–7158 (2005).

    CAS  PubMed  Google Scholar 

  49. Tropea, D., Caleo, M. & Maffei, L. Synergistic effects of brain-derived neurotrophic factor and chondroitinase ABC on retinal fiber sprouting after denervation of the superior colliculus in adult rats. J. Neurosci. 23, 7034–7044 (2003).

    CAS  PubMed  Google Scholar 

  50. Massey, J. M. et al. Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J. Neurosci. 26, 4406–4414 (2006).

    CAS  PubMed  Google Scholar 

  51. Cafferty, W. B., Bradbury, E. J., Jones, M., Lidierth, M. & McMahon, S. B. Chondroitinase ABC-mediated restitution of electrophysiological function after deafferentation. Soc. Neurosci. Abstr. 619.3 (2004).

  52. Romero, M. I. et al. Extensive sprouting of sensory afferents and hyperalgesia induced by conditional expression of nerve growth factor in the adult spinal cord. J. Neurosci. 20, 4435–4445 (2000).

    CAS  PubMed  Google Scholar 

  53. Weaver, L. C., Marsh, D. R., Gris, D., Brown, A. & Dekaban, G. A. Autonomic dysreflexia after spinal cord injury: central mechanisms and strategies for prevention. Prog. Brain Res. 152, 245–263 (2006).

    PubMed  Google Scholar 

  54. Hofstetter, C. P. et al. Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nature Neurosci. 8, 346–353 (2005).

    CAS  PubMed  Google Scholar 

  55. Siddall, P. J., McClelland, J. M., Rutkowski, S. B. & Cousins, M. J. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103, 249–257 (2003).

    PubMed  Google Scholar 

  56. Balazy, T. E. Clinical management of chronic pain in spinal cord injury. Clin. J. Pain 8, 102–110 (1992).

    CAS  PubMed  Google Scholar 

  57. Adams, M. M. & Hicks, A. L. Spasticity after spinal cord injury. Spinal Cord. 43, 577–586 (2005).

    CAS  PubMed  Google Scholar 

  58. Karlsson, A. K. Autonomic dysfunction in spinal cord injury: clinical presentation of symptoms and signs. Prog. Brain Res. 152, 1–8 (2006).

    PubMed  Google Scholar 

  59. Burchiel, K. J. & Hsu, F. P. Pain and spasticity after spinal cord injury: mechanisms and treatment. Spine 26, S146–S160 (2001).

    CAS  PubMed  Google Scholar 

  60. Rossignol, S. Locomotion and its recovery after spinal injury. Curr. Opin. Neurobiol. 10, 708–716 (2000).

    CAS  PubMed  Google Scholar 

  61. Behrman, A. L. & Harkema, S. J. Locomotor training after human spinal cord injury: a series of case studies. Phys. Ther. 80, 688–700 (2000).

    CAS  PubMed  Google Scholar 

  62. Fouad, K. & Pearson, K. Restoring walking after spinal cord injury. Prog. Neurobiol. 73, 107–126 (2004).

    PubMed  Google Scholar 

  63. Ramer, M. S., Bradbury, E. J. & McMahon, S. B. Nerve growth factor induces P2X(3) expression in sensory neurons. J. Neurochem. 77, 864–875 (2001).

    CAS  PubMed  Google Scholar 

  64. Pezet, S., Malcangio, M. & McMahon, S. B. BDNF: a neuromodulator in nociceptive pathways? Brain Res. Brain Res. Rev. 40, 240–249 (2002).

    CAS  PubMed  Google Scholar 

  65. McMahon, S. B. & Koltzenburg, M. Textbook of Pain 5th edn (Elsevier, London, 2005).

    Google Scholar 

  66. Waxman, S. G. Demyelination in spinal cord injury. J. Neurol. Sci. 91, 1–14 (1989).

    CAS  PubMed  Google Scholar 

  67. Guest, J. D., Hiester, E. D. & Bunge, R. P. Demyelination and Schwann cell responses adjacent to injury epicenter cavities following chronic human spinal cord injury. Exp. Neurol. 192, 384–393 (2005).

    CAS  PubMed  Google Scholar 

  68. Cao, Q. et al. Functional and electrophysiological changes after graded traumatic spinal cord injury in adult rat. Exp. Neurol. 191, S3–S16 (2005).

    PubMed  Google Scholar 

  69. McTigue, D. M., Horner, P. J., Stokes, B. T. & Gage, F. H. Neurotrophin-3 and brain-derived neurotrophic factor induce oligodendrocyte proliferation and myelination of regenerating axons in the contused adult rat spinal cord. J. Neurosci. 18, 5354–5365 (1998).

    CAS  PubMed  Google Scholar 

  70. Hayes, K. C. et al. 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. J. Neurotrauma 11, 433–446 (1994).

    CAS  PubMed  Google Scholar 

  71. Hayes, K. C. et al. Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Paraplegia 31, 216–224 (1993).

    CAS  PubMed  Google Scholar 

  72. Keirstead, H. S. et al. Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury. J. Neurosci. 25, 4694–4705 (2005).

    CAS  PubMed  Google Scholar 

  73. Cao, Q. et al. Functional recovery in traumatic spinal cord injury after transplantation of multineurotrophin-expressing glial-restricted precursor cells. J. Neurosci. 25, 6947–6957 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Williams, B., Terry, A. F., Jones, F. & McSweeney, T. Syringomyelia as a sequel to traumatic paraplegia. Paraplegia 19, 67–80 (1981).

    CAS  PubMed  Google Scholar 

  75. Bunge, R. P., Puckett, W. R. & Hiester, E. D. Observations on the pathology of several types of human spinal cord injury, with emphasis on the astrocyte response to penetrating injuries. Adv. Neurol. 72, 305–315 (1997).

    CAS  PubMed  Google Scholar 

  76. Fitch, M. T., Doller, C., Combs, C. K., Landreth, G. E. & Silver, J. Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J. Neurosci. 19, 8182–8198 (1999).

    CAS  PubMed  Google Scholar 

  77. Dusart, I. & Schwab, M. E. Secondary cell death and the inflammatory reaction after dorsal hemisection of the rat spinal cord. Eur. J. Neurosci. 6, 712–724 (1994).

    CAS  PubMed  Google Scholar 

  78. Liu, X. Z. et al. Neuronal and glial apoptosis after traumatic spinal cord injury. J. Neurosci. 17, 5395–5406 (1997).

    CAS  PubMed  Google Scholar 

  79. Jones, T. B., McDaniel, E. E. & Popovich, P. G. Inflammatory-mediated injury and repair in the traumatically injured spinal cord. Curr. Pharm. Des. 11, 1223–1236 (2005).

    CAS  PubMed  Google Scholar 

  80. Popovich, P. G. et al. Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp. Neurol. 158, 351–365 (1999).

    CAS  PubMed  Google Scholar 

  81. Oudega, M., Vargas, C. G., Weber, A. B., Kleitman, N. & Bunge, M. B. Long-term effects of methylprednisolone following transection of adult rat spinal cord. Eur. J. Neurosci. 11, 2453–2464 (1999).

    CAS  PubMed  Google Scholar 

  82. Young, W. Methylprednisolone treatment of acute spinal cord injury: an introduction. J. Neurotrauma. 8, S43–S46 (1991).

    PubMed  Google Scholar 

  83. Christensen, M. D. & Hulsebosch, C. E. Chronic central pain after spinal cord injury. J. Neurotrauma 14, 517–537 (1997).

    CAS  PubMed  Google Scholar 

  84. Hains, B. C. et al. Upregulation of sodium channel Nav1. 3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J. Neurosci. 23, 8881–8892 (2003).

    CAS  PubMed  Google Scholar 

  85. Nesic, O. et al. Transcriptional profiling of spinal cord injury-induced central neuropathic pain. J. Neurochem. 95, 998–1014 (2005).

    CAS  PubMed  Google Scholar 

  86. Crown, E. D. et al. Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp. Neurol. 199, 397–407 (2006).

    CAS  PubMed  Google Scholar 

  87. McMahon, S. B., Cafferty, W. B. & Marchand, F. Immune and glial cell factors as pain mediators and modulators. Exp. Neurol. 192, 444–462 (2005).

    CAS  PubMed  Google Scholar 

  88. Hains, B. C. & Waxman, S. G. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J. Neurosci. 26, 4308–4317 (2006).

    CAS  PubMed  Google Scholar 

  89. Basso, D. M., Beattie, M. S. & Bresnahan, J. C. A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1–21 (1995).

    CAS  PubMed  Google Scholar 

  90. Webb, A. A. & Muir, G. D. Compensatory locomotor adjustments of rats with cervical or thoracic spinal cord hemisections. J. Neurotrauma 19, 239–256 (2002).

    PubMed  Google Scholar 

  91. Piecharka, D. M., Kleim, J. A. & Whishaw, I. Q. Limits on recovery in the corticospinal tract of the rat: partial lesions impair skilled reaching and the topographic representation of the forelimb in motor cortex. Brain Res. Bull. 66, 203–211 (2005).

    PubMed  Google Scholar 

  92. Bruce, J. C., Oatway, M. A. & Weaver, L. C. Chronic pain after clip-compression injury of the rat spinal cord. Exp. Neurol. 178, 33–48 (2002).

    PubMed  Google Scholar 

  93. Lindsey, A. E. et al. An analysis of changes in sensory thresholds to mild tactile and cold stimuli after experimental spinal cord injury in the rat. Neurorehabil. Neural Repair 14, 287–300 (2000).

    CAS  PubMed  Google Scholar 

  94. Krenz, N. R., Meakin, S. O., Krassioukov, A. V. & Weaver, L. C. Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury. J. Neurosci. 19, 7405–7414 (1999).

    CAS  PubMed  Google Scholar 

  95. Weaver, L. C. et al. Autonomic dysreflexia and primary afferent sprouting after clip-compression injury of the rat spinal cord. J. Neurotrauma 18, 1107–1119 (2001).

    CAS  PubMed  Google Scholar 

  96. Rabchevsky, A. G. Segmental organization of spinal reflexes mediating autonomic dysreflexia after spinal cord injury. Prog. Brain Res. 152, 265–274 (2006).

    PubMed  PubMed Central  Google Scholar 

  97. de Groat, W. C. et al. Modification of urinary bladder function after spinal cord injury. Adv. Neurol. 72, 347–364 (1997).

    CAS  PubMed  Google Scholar 

  98. Elliott, S. L. Problems of sexual function after spinal cord injury. Prog. Brain Res. 152, 387–399 (2006).

    PubMed  Google Scholar 

  99. Potter, P. J. Disordered control of the urinary bladder after human spinal cord injury: what are the problems? Prog. Brain Res. 152, 51–57 (2006).

    PubMed  Google Scholar 

  100. Caroni, P., Savio, T. & Schwab, M. E. Central nervous system regeneration: oligodendrocytes and myelin as non-permissive substrates for neurite growth. Prog. Brain Res. 78, 363–370 (1988).

    CAS  PubMed  Google Scholar 

  101. Chen, M. S. et al. Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1 Nature 403, 434–439 (2000).

    CAS  PubMed  Google Scholar 

  102. Prinjha, R. et al. Inhibitor of neurite outgrowth in humans. Nature 403, 383–384 (2000).

    CAS  PubMed  Google Scholar 

  103. GrandPre, T., Nakamura, F., Vartanian, T. & Strittmatter, S. M. Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444 (2000).

    CAS  PubMed  Google Scholar 

  104. Schnell, L. & Schwab, M. E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269–272 (1990).

    CAS  PubMed  Google Scholar 

  105. Woolf, C. J. No Nogo: now where to go? Neuron 38, 153–156 (2003).

    CAS  PubMed  Google Scholar 

  106. Schwab, M. E. Nogo and axon regeneration. Curr. Opin. Neurobiol. 14, 118–124 (2004).

    CAS  PubMed  Google Scholar 

  107. McGee, A. W. & Strittmatter, S. M. The Nogo-66 receptor: focusing myelin inhibition of axon regeneration. Trends Neurosci. 26, 193–198 (2003).

    CAS  PubMed  Google Scholar 

  108. Mukhopadhyay, G., Doherty, P., Walsh, F. S., Crocker, P. R. & Filbin, M. T. A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13, 757–767 (1994).

    CAS  PubMed  Google Scholar 

  109. Wang, K. C. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944 (2002).

    CAS  PubMed  Google Scholar 

  110. Jones, L. L., Margolis, R. U. & Tuszynski, M. H. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp. Neurol. 182, 399–411 (2003).

    CAS  PubMed  Google Scholar 

  111. Tang, X., Davies, J. E. & Davies, S. J. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue. J. Neurosci. Res. 71, 427–444 (2003).

    CAS  PubMed  Google Scholar 

  112. Silver, J. & Miller, J. H. Regeneration beyond the glial scar. Nature Rev. Neurosci. 5, 146–156 (2004).

    CAS  Google Scholar 

  113. Smith-Thomas, L. C. et al. An inhibitor of neurite outgrowth produced by astrocytes. J. Cell Sci. 107, 1687–1695 (1994).

    CAS  PubMed  Google Scholar 

  114. Dou, C. L. & Levine, J. M. Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. J. Neurosci. 14, 7616–7628 (1994).

    CAS  PubMed  Google Scholar 

  115. Snow, D. M., Lemmon, V., Carrino, D. A., Caplan, A. I. & Silver, J. Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp. Neurol. 109, 111–130 (1990).

    CAS  PubMed  Google Scholar 

  116. Davies, S. J., Goucher, D. R., Doller, C. & Silver, J. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 5810–5822 (1999).

    CAS  PubMed  Google Scholar 

  117. McKeon, R. J., Hoke, A. & Silver, J. Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp. Neurol. 136, 32–43 (1995).

    CAS  PubMed  Google Scholar 

  118. Moon, L. D., Asher, R. A., Rhodes, K. E. & Fawcett, J. W. Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nature Neurosci. 4, 465–466 (2001).

    CAS  PubMed  Google Scholar 

  119. Caggiano, A. O., Zimber, M. P., Ganguly, A., Blight, A. R. & Gruskin, E. A. Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. J. Neurotrauma 22, 226–239 (2005).

    PubMed  Google Scholar 

  120. Pasterkamp, R. J. et al. Expression of the gene encoding the chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS. Mol. Cell. Neurosci. 13, 143–166 (1999).

    CAS  PubMed  Google Scholar 

  121. Bundesen, L. Q., Scheel, T. A., Bregman, B. S. & Kromer, L. F. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J. Neurosci. 23, 7789–7800 (2003).

    CAS  PubMed  Google Scholar 

  122. Chau, C. H. et al. Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. FASEB J. 18, 194–196 (2004).

    CAS  PubMed  Google Scholar 

  123. Ikegami, T. et al. Chondroitinase ABC combined with neural stem/progenitor cell transplantation enhances graft cell migration and outgrowth of growth-associated protein-43-positive fibers after rat spinal cord injury. Eur. J. Neurosci. 22, 3036–3046 (2005).

    PubMed  Google Scholar 

  124. Fouad, K. et al. Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord. J. Neurosci. 25, 1169–1178 (2005).

    CAS  PubMed  Google Scholar 

  125. Yick, L. W., So, K. F., Cheung, P. T. & Wu, W. T. Lithium chloride reinforces the regeneration-promoting effect of chondroitinase ABC on rubrospinal neurons after spinal cord injury. J. Neurotrauma 21, 932–943 (2004).

    PubMed  Google Scholar 

  126. Xu, X. M., Guenard, V., Kleitman, N., Aebischer, P. & Bunge, M. B. A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp. Neurol. 134, 261–272 (1995).

    CAS  PubMed  Google Scholar 

  127. Menei, P., Montero-Menei, C., Whittemore, S. R., Bunge, R. P. & Bunge, M. B. Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur. J. Neurosci. 10, 607–621 (1998).

    CAS  PubMed  Google Scholar 

  128. Murray, M. & Fischer, I. Transplantation and gene therapy: combined approaches for repair of spinal cord injury. Neuroscientist 7, 28–41 (2001).

    CAS  PubMed  Google Scholar 

  129. Jones, L. L., Oudega, M., Bunge, M. B. & Tuszynski, M. H. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J. Physiol. 533, 83–89 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Lu, P., Yang, H., Jones, L. L., Filbin, M. T. & Tuszynski, M. H. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J. Neurosci. 24, 6402–6409 (2004).

    CAS  PubMed  Google Scholar 

  131. Pearse, D. D. et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nature Med. 10, 610–616 (2004).

    CAS  PubMed  Google Scholar 

  132. Martin, J. H. Neuroanatomy: Text and Atlas 2nd edn (Appleton & Lange, Stamford, Connecticut, 1996).

    Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by grants from the Medical Research Council and the Wellcome Trust, whom we would like to thank. We would also like to thank T. Boucher and D. Bennett for advice on the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen B. McMahon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Bradbury's homepage

McMahon's homepage

Glossary

Allodynia

Pain from stimuli that are not normally painful.

Chondroitinase ABC

(ChABC). A bacterial enzyme that cleaves the sugar (glycosaminoglycan) chains from proteoglycan molecules, rendering them less inhibitory to growth.

Contact-placing responses

In response to light contact of the foot an animal will lift its limb and place it on a surface for support.

Glial scar

Following CNS injury, activated glial cells form a meshwork of interweaving processes that surround the lesion site. Scarring is important for sealing the wound but can also act as an impenetrable barrier to regeneration.

H-reflex

A monosynaptic reflex elicited by electrically stimulating a nerve with an electric stimulus.

Immediate-early genes

A family of genes that share the characteristic of having their expression rapidly and transiently induced on stimulation.

Preconditioning

A protective effect from injury achieved by a previous insult (thought to be mediated by pro-regenerative changes in the cell body triggered by the insult).

Pyramidotomy

Transection of the corticospinal tract (CST) at the level of the medullary pyramids in the brainstem. A unilateral pyramidotomy lesions the CST on one side, leaving the other side intact (thereby denervating one side of the spinal cord).

Rhizotomy

An injury to the spinal dorsal roots that results in an interruption of sensory input from the PNS into the spinal cord.

Transcranial magnetic stimulation

Involves creating a strong localized transient magnetic field that induces current flow in underlying neural tissue, causing a temporary change in activity in small regions of the brain.

Wallerian degeneration

Degeneration that occurs after axonal injury in the distal segment of a nerve fibre – the part no longer connected to the cell body.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bradbury, E., McMahon, S. Spinal cord repair strategies: why do they work?. Nat Rev Neurosci 7, 644–653 (2006). https://doi.org/10.1038/nrn1964

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1964

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing