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Review
. 2008 Feb;209(2):321-32.
doi: 10.1016/j.expneurol.2007.06.020. Epub 2007 Aug 27.

The Role of Cyclic AMP Signaling in Promoting Axonal Regeneration After Spinal Cord Injury

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Free PMC article
Review

The Role of Cyclic AMP Signaling in Promoting Axonal Regeneration After Spinal Cord Injury

Sari S Hannila et al. Exp Neurol. .
Free PMC article

Abstract

The failure of axons to regenerate after spinal cord injury remains one of the greatest challenges facing both medicine and neuroscience, but in the last 20 years there have been tremendous advances in the field of spinal cord injury repair. One of the most important of these has been the identification of inhibitory proteins in CNS myelin, and this has led to the development of strategies that will enable axons to overcome myelin inhibition. Elevation of intracellular cyclic AMP (cAMP) has been one of the most successful of these strategies, and in this review we examine how cAMP signaling promotes axonal regeneration in the CNS. Intracellular cAMP levels can be increased through a peripheral conditioning lesion, administration of cAMP analogues, priming with neurotrophins or treatment with the phosphodiesterase inhibitor rolipram, and each of these methods has been shown to overcome myelin inhibition both in vitro and in vivo. It is now known that the effects of cAMP are transcription dependent, and that cAMP-mediated activation of CREB leads to upregulated expression of genes such as arginase I and interleukin-6. The products of these genes have been shown to directly promote axonal regeneration, which raises the possibility that other cAMP-regulated genes could yield additional agents that would be beneficial in the treatment of spinal cord injury. Further study of these genes, in combination with human clinical trials of existing agents such as rolipram, would allow the therapeutic potential of cAMP to be fully realized.

Figures

Figure 1
Figure 1
Schematic representation of intracellular signaling pathways activated by neurotrophins and their role in overcoming inhibition by CNS myelin. Priming with neurotrophins activates Trk receptors and Erk, which in turn produces a transient inhibition of PDE4 activity. This causes intracellular cAMP levels to rise and upon reaching a threshold level, cAMP will activate PKA and initiate transcription by CREB. These events allow primed neurons to overcome inhibition mediated by MAG, Nogo-A, and OMgp binding to the receptor complex consisting of NgR1 or NgR2, p75NTR or TROY, and LINGO-1. Myelin inhibitors also activate Gi/Go, which inactivates adenylate cyclase and inhibits cAMP synthesis. When neurotrophins are added directly to neurons in the presence of myelin, intracellular cAMP rises, but the threshold level cannot be reached due to the activity of Gi/Go, and as a result, inhibition persists. Administration of PTX in conjunction with neurotrophins blocks the effects of Gi/Go and allows neurons to overcome inhibition in the absence of priming.
Figure 2
Figure 2
Rolipram promotes growth of serotonergic axons, reduces astrogliosis, and improves functional recovery after spinal cord injury. Few serotonergic fibers (arrowheads) are present within the embryonic spinal cord tissue grafts of vehicle-treated animals (A) at 6−8 weeks after spinal cord hemisection, but in animals that received rolipram, growth of serotonergic axons is significantly increased (B, C). Animals treated with rolipram (E) also show significantly less GFAP staining within the tissue grafts when compared to animals that received vehicle alone (D), and this is indicative of a reduction in astrogliosis. Lastly, animals treated with rolipram show improved functional recovery, as demonstrated by a significant decrease in paw placement errors (F). Scale bars = 50 μm. (Copyright 2004 National Academy of Sciences, U.S.A)
Figure 3
Figure 3
Rolipram in combination with Schwann cell transplantation and dbcAMP promotes axonal sparing and myelination after spinal cord contusion injury. Transverse sections of control spinal cords (A) showed extensive cavitation at 11 weeks after injury, but in animals that received Schwann cell grafts (B) or Schwann cells plus dbcAMP and rolipram (C) there was greater tissue preservation. Analysis at higher magnification revealed that densities of myelinated axons were significantly increased in animals that received Schwann cells, dbcAMP and rolipram (F, I) or Schwann cells alone (E, H) compared to control animals (D, G). (Adapted by permission from Macmillan Publishers Ltd.: Pearse, D. D., Pereira, F. C., Marcillo, A. E., Bates, M. L., Berrocal, Y. A., Filbin, M. T., and Bunge, M. B., cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Nature Medicine 10, 610−616, copyright 2004.)

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