The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury

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.

A Model for Sealing Plasmalemmal Damage in Neurons and Other Eukaryotic Cells

“…2B,C), but cannot completely substitute for Ca 2ϩ (Fig. 3B) cAMP increases vesicular interactions in Golgi trafficking, growth cone extension, and transmitter release at synapses (Yoshihara et al, 2000;Sedej et al, 2005; for review see Hannila and Filbin, 2008). cAMP and cAMP activated proteins increase plasmalemmal sealing at PC times up to 20 min, including at 0 min PC, even when the bathing solution contains no Ca 2ϩ ( Fig.…”

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

“…Therefore, the potential PDE4 inhibitors may be an eicient alternative strategy to play antidepressant action especially in depressive disorder induced by inflammation. Consistent with this hypothesis, the previous studies have demonstrated that rolipram reduces neuroinflammation and promotes axonal regeneration and functional recuperation following spinal cord injury [96][97][98]; [62]. More evidence have shown that PDE4 inhibitor rolipram reduces the production of proinflammatory cytokines and modulates the activity of cAMP-mediated signaling and thus regulates CREB phosphorylation and the downstream efectors [99]; [62,68], showing that potential PDE4 inhibitors may be suitable to antagonize psychiatric disorders.…”

The Development of Developmental Neuroscience

“…This work led to two streams of investigation, the second rather unresolved to this day: First, while mature axons can regrow, they do so at a disappointingly slow rate, and they lack the molecular components of young growing axons. Now we know that molecular brakes preventing mature axon regrowth include repressors of the m-TOR pathway, cAMP, and other transcription factors (Hannila and Filbin, 2008;Park et al, 2008). Second, we have long known that the environment of the site of injury, adult neuropil, and tracts are rife with glia that impede regrowth.…”