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.

  • Article
  • Published:

cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury

Nature Medicine volume 10, pages 610–616 (2004)Cite this article

Abstract

Central neurons regenerate axons if a permissive environment is provided; after spinal cord injury, however, inhibitory molecules are present that make the local environment nonpermissive. A promising new strategy for inducing neurons to overcome inhibitory signals is to activate cAMP signaling. Here we show thatcAMP levels fall in the rostral spinal cord, sensorimotor cortex and brainstem after spinal cord contusion. Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination. Furthermore, combining rolipram with an injection of db-cAMP near the graft not only prevents the drop in cAMP levels but increases them above those in uninjured controls. This further enhances axonal sparing and myelination, promotes growth of serotonergic fibers into and beyond grafts, and significantly improves locomotion. These findings show that cAMP levels are key for protection, growth and myelination of injured CNS axons in vivo and recovery of function.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Rolipram and db-cAMP prevent SCI-induced reductions in cAMP.
Figure 2: Acute rolipram inhibits TNF-α, but not IL-1β, production hours after SCI.
Figure 3: Elevation of cAMP promotes central myelinated axon preservation, axonal growth regeneration and SC myelination.
Figure 4: Elevation of cAMP supports supraspinal axon sparing and growth.
Figure 5: Elevation of cAMP promotes serotonergic growth into and beyond SC grafts.
Figure 6: Improved functional recovery after prolonged cAMP elevation.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Fawcett, J.W. & Asher, R.A. The glial scar and central nervous system repair. Brain Res. Bull. 49, 377–391 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Richardson, P.M., McGuinness, U.M. & Aguayo, A.J. Axons from CNS neurons regenerate into PNS grafts. Nature 284, 264–265 (1980).

    Article  CAS  Google Scholar 

  5. David, S. & Aguayo, A.J. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214, 931–933 (1981).

    Article  CAS  Google Scholar 

  6. Bunge, M.B. Bridging areas of injury in the spinal cord. Neuroscientist 7, 325–339 (2001).

    Article  CAS  Google Scholar 

  7. Bunge, M.B. Bridging the transected or contused adult rat spinal cord with Schwann cell and olfactory ensheathing glia transplants. Progr. Brain Res. 137, 275–282. (2002)

    Article  Google Scholar 

  8. Takami, T. et al. Schwann cell but not olfactory ensheathing glia transplants improve hindlimb locomotor performance in the moderately contused adult rat thoracic spinal cord. J. Neurosci. 22, 6670–6681 (2002).

    Article  CAS  Google Scholar 

  9. Song, H.J., Ming, G.L. & Poo, M.M. cAMP-induced switching in turning direction of nerve growth cones. Nature 388, 275–279 (1997).

    Article  CAS  Google Scholar 

  10. Ming, G.L. et al. cAMP-dependent growth cone guidance by netrin-1. Neuron 19, 1225–1235 (1997).

    Article  CAS  Google Scholar 

  11. Cai, D. et al. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J. Neurosci. 21, 4731–4739 (2001).

    Article  CAS  Google Scholar 

  12. Souness, J.E., Aldous, D. & Sargent, C. Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology 47, 127–162 (2000).

    Article  CAS  Google Scholar 

  13. Schultz, J.E. & Folkers, G. Unusual stereospecificity of the potential antidepressant rolipram on the cyclic AMP generating system from rat brain cortex. Pharmacopsychiatry 21, 83–86 (1988).

    Article  CAS  Google Scholar 

  14. Lee, Y.B. et al. Role of tumor necrosis factor-α in neuronal and glial apoptosis after spinal cord injury. Exp. Neurol. 166, 190–195 (2000).

    Article  CAS  Google Scholar 

  15. Nesic, O. et al. IL-1 receptor antagonist prevents apoptosis and caspase-3 activation after spinal cord injury. J. Neurotrauma 18, 947–956 (2001).

    Article  CAS  Google Scholar 

  16. Akassoglou, K. et al. Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am. J. Pathol. 153, 801–813 (1998).

    Article  CAS  Google Scholar 

  17. Tator, C.H. Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol. 5, 407–413 (1995).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. Meyer–Franke, A., Kaplan, M.R., Pfrieger, F.W. & Barres, B.A. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15, 805–819 (1995).

    Article  Google Scholar 

  20. Nijjar, M.S. & Nijjar, S.S. Domoic acid–induced neurodegeneration resulting in memory loss is mediated by Ca2+ overload and inhibition of Ca2+ calmodulin-stimulated adenylate cyclase in rat brain. Int. J. Mol. Med. 6, 377–389 (2000).

    CAS  PubMed  Google Scholar 

  21. Troadec, J.D. et al. Activation of the mitogen-activated protein kinase (ERK(1/2)) signaling pathway by cyclic AMP potentiates the neuroprotective effect of the neurotransmitter noradrenaline on dopaminergic neurons. Mol. Pharmacol. 62, 1043–1052 (2002).

    Article  CAS  Google Scholar 

  22. Nuydens, R., Nuyens, R., Cornelissen, F. & Geerts, H. The fast axonal transport in hippocampal neurones is acutely enhanced by db-cAMP. Neuroreport 4, 179–182 (1993).

    Article  CAS  Google Scholar 

  23. Azhderian, E.M., Hefner, D., Lin, C.H., Kaczmarek, L.K. & Forscher, P. Cyclic AMP modulates fast axonal transport in Aplysia bag cell neurons by increasing the probability of single organelle movement. Neuron 12, 1223–1233 (1994).

    Article  CAS  Google Scholar 

  24. Neumann, H. Molecular mechanisms of axonal damage in inflammatory central nervous system diseases. Curr. Opin. Neurol. 16, 267–273 (2003).

    Article  CAS  Google Scholar 

  25. Kammer, G.M. The adenylate cyclase–cAMP–protein kinase A pathway and regulation of the immune response. Immunol. Today 9, 222–229 (1988).

    Article  CAS  Google Scholar 

  26. Zidek, Z. Adenosine–cyclic AMP pathways and cytokine expression. Eur. Cytokine Netw. 10, 319–328 (1999).

    CAS  PubMed  Google Scholar 

  27. Xu, J. et al. Methylprednisolone inhibition of TNF-α expression and NF-κB activation after spinal cord injury in rats. Brain Res. Mol. Brain Res. 59, 135–142 (1998).

    Article  CAS  Google Scholar 

  28. Bethea, J.R. et al. Systemically administered interleukin-10 reduces tumor necrosis factor-α production and significantly improves functional recovery following traumatic spinal cord injury in rats. J. Neurotrauma 16, 851–863 (1999).

    Article  CAS  Google Scholar 

  29. Morgan, L., Jessen, K.R. & Mirsky, R. The effects of cAMP on differentiation of cultured Schwann cells: progression from an early phenotype (04+) to a myelin phenotype (P0+, GFAP−, N-CAM−, NGF-receptor−) depends on growth inhibition. J. Cell Biol. 112, 457–467 (1991).

    Article  CAS  Google Scholar 

  30. Morgan, L., Jessen, K.R. & Mirsky, R. Negative regulation of the P0 gene in Schwann cells: suppression of P0 mRNA and protein induction in cultured Schwann cells by FGF2 and TGFβ1, TGFβ2 and TGFβ3. Development 120, 1399–1409 (1994).

    CAS  PubMed  Google Scholar 

  31. Howe, D.G. & McCarthy, K.D. Retroviral inhibition of cAMP-dependent protein kinase inhibits myelination but not Schwann cell mitosis stimulated by interaction with neurons. J. Neurosci. 20, 3513–3521 (2000).

    Article  CAS  Google Scholar 

  32. Viala, D. & Buser, P. The effects of DOPA and 5-HTP on rhythmic efferent discharges in hind limb nerves in the rabbit. Brain Res. 12, 437–443 (1969).

    Article  CAS  Google Scholar 

  33. Ribotta, M.G. et al. Activation of locomotion in adult chronic spinal rats is achieved by transplantation of embryonic raphe cells reinnervating a precise lumbar level. J. Neurosci. 20, 5144–5152 (2000).

    Article  CAS  Google Scholar 

  34. Barbeau, H. & Rossignol, S. Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs. Brain Res. 546, 250–260 (1991).

    Article  CAS  Google Scholar 

  35. Davies, S.J. et al. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680–683 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Yamamoto, M. et al. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and low-affinity nerve growth factor receptor (LNGFR) mRNA levels in cultured rat Schwann cells; differential time- and dose-dependent regulation by cAMP. Neurosci. Lett. 152, 37–40 (1993).

    Article  CAS  Google Scholar 

  38. Neumann, S., Bradke, F., Tessier-Lavigne, M. & Basbaum, A.I. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34, 885–893 (2002).

    Article  CAS  Google Scholar 

  39. Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 1–9 (2002).

    Article  Google Scholar 

  40. Morrissey, T.K., Kleitman, N. & Bunge, R.P. Isolation and functional characterization of Schwann cells derived from adult peripheral nerve. J. Neurosci. 11, 2433–2442 (1991).

    Article  CAS  Google Scholar 

  41. Gruner, J.A. A monitored contusion model of spinal cord injury in the rat. J. Neurotrauma 9, 123–128 (1992).

    Article  CAS  Google Scholar 

  42. Xu, X.M., Guenard, V., Kleitman, N. & Bunge, M.B. Axonal regeneration into Schwann cell–seeded guidance channels grafted into transected adult rat spinal cord. J. Comp. Neurol. 351, 145–160 (1995).

    Article  CAS  Google Scholar 

  43. West, N.R. & Collins, G.H. Cellular changes during repair of a cryogenic spinal cord injury in the rat: an electron microscopic study. J. Neuropathol. Exp. Neurol. 48, 94–108 (1989).

    Article  CAS  Google Scholar 

  44. Bunge, M.B., Holets, V.R., Bates, M.L., Clarke, T.S. & Watson, B.D. Characterization of photochemically induced spinal cord injury in the rat by light and electron microscopy. Exp. Neurol. 127, 76–93 (1994).

    Article  CAS  Google Scholar 

  45. Ludwin, S.K. Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab. Invest. 39, 597–612 (1978).

    CAS  PubMed  Google Scholar 

  46. 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).

    Article  CAS  Google Scholar 

  47. Metz, G.A., Merkler, D., Dietz, V., Schwab, M.E. & Fouad, K. Efficient testing of motor function in spinal cord injured rats. Brain Res. 883, 165–177 (2000).

    Article  CAS  Google Scholar 

  48. de Medinaceli, L., Freed, W.J. & Wyatt, R.J. An index of the functional condition of rat sciatic nerve based on measurements made from walking tracks. Exp. Neurol. 77, 634–643 (1982).

    Article  CAS  Google Scholar 

  49. Scheff, S.W., Saucier, D.A. & Cain, M.E. A statistical method for analyzing rating scale data: the BBB locomotor score. J. Neurotrauma 19, 1251–1260 (2002).

    Article  Google Scholar 

  50. Cohen, J. Statistical Power Analysis for the Behavioral Sciences edn. 2 (Erlbaum, Hillsdale, New Jersey, USA, 1988).

    Google Scholar 

Download references

Acknowledgements

We thank R. Puzis and M. Perez for help with immunochemistry and ELISAs; Y. Pressman for SC culturing; B. Frydel, M. Garg and A. Stolyarova for aid with image analysis; G. Ruenes, L. Rusakova, W. Chen and X. Zhang for tissue embedding and sectioning; Y. Cruz for expertise in statistical analyses; E. Nikulina for helpful discussions on rolipram administration; R. Abril, D. Koivisto and K. Loor for help with animal care and behavioral testing; and P. Diaz and S. Castro for inducing contusion injuries and drug treatment. Anti-p75 (192 IgG) was a gift from E. Shooter (Stanford University, Stanford, California, USA). This work was funded by the Christopher Reeve Paralysis Foundation, NINDS09923 and 38665, The Miami Project and the Buoniconti Fund. D.D.P. is a Christopher Reeve Paralysis Foundation Consortium Associate. M.B.B. is the Christine E. Lynn Distinguished Professor of Neuroscience.

Author information

Authors and Affiliations

  1. The Miami Project to Cure Paralysis, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, 33136, Florida, USA

    Damien D Pearse, Alexander E Marcillo, Margaret L Bates, Yerko A Berrocal & Mary Bartlett Bunge

  2. Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 2415, Sao Paulo, 05508-900, CEP, Brazil

    Francisco C Pereira

  3. Biology Department, Hunter College, 695 Park Ave., New York, 10021, New York, USA

    Marie T Filbin

  4. Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Mary Bartlett Bunge

  5. Department of Neurological Surgery, University of Miami School of Medicine, Miami, 33136, Florida, USA

    Mary Bartlett Bunge

Authors
  1. Damien D Pearse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francisco C Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander E Marcillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaret L Bates
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yerko A Berrocal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marie T Filbin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary Bartlett Bunge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Damien D Pearse.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pearse, D., Pereira, F., Marcillo, A. et al. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nat Med 10, 610–616 (2004). https://doi.org/10.1038/nm1056

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1056

This article is cited by

Search

Advanced 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