Review articleThe role of cAMP and its downstream targets in neurite growth in the adult nervous system
Introduction
Ever since David and Aguayo [1] first demonstrated that injured central nervous system (CNS) axons can grow into a peripheral nerve graft, a major question has been: why do CNS axons not regenerate within the injured CNS? Three streams of research tackled this question. One stream examined whether the lack of CNS regeneration was due to an inhibitory environment. This research later identified inhibitory factors for neurite outgrowth including myelin associated inhibitors [2], and chondroitin sulfate proteoglycans (CSPGs) in the glial scar and the perineuronal net [3], [4]. The second stream examined whether reduced CNS regeneration was due to a lack of neurotrophic support resulting in the neurons not having the ability to regrow, as proposed by Aguayo himself [1]. The third stream examined the question of whether age related changes might influence the decline in neuronal growth abilities [5], [6]. These streams of research led to three main treatment strategies. Some laboratories attempted to neutralize neurite growth inhibitors (e.g., MAG [7] or Nogo [8], [9];, and CSPGs [10], [11]), while others augmented neurotrophic support by adding growth factors like brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or glial cell-derived neurotrophic factor (GDNF), to the injured spinal cord [12], [13], [14], [15], [16] (Fig. 1). Alternatively, some groups attempted to modulate intracellular signalling pathways with the idea to recreate conditions of the developing CNS in order to allow injured neurons to regrow [5], [6], [12], [17], [18]. As a result of all of this research, it is now well accepted that a combination of all of three factors (growth inhibitors, in sufficient of growth promoting factors and developmental changes) are responsible for the limited neurite outgrowth and repair after a spinal cord injury (SCI) in adult mammals.
With many intrinsic and extrinsic factors converging to prevent regeneration (growth at the tip of lesioned axons) and plasticity (e.g., growth of new collaterals) after SCI, there is a major effort to identify whether there is a common cell signalling pathway responsible for inhibiting neurite growth. This effort has resulted in the knowledge that both the intrinsic and extrinsic factors inhibiting axonal growth after SCI seem to converge on a number of signalling pathways associated with cAMP, calcium/calmodulin, Ras homolog gene family member A (RhoA), and the mechanistic target of rapamycin (mTOR). A number of recent reviews have focused on roles of RhoA [18], [19] and mTOR [6], [20] in axon growth and regeneration; this review will focus on cAMP and its downstream effectors. Specifically, we will discuss the relationship between cAMP and neurite outgrowth in the adult CNS, recently identified cAMP cell signalling pathways linked to axonal growth after SCI, and possible treatment strategies aimed to activate relevant cAMP dependent pathways.
Section snippets
The role of cAMP in neurite growth
In the embryonic CNS, cAMP levels are high and are linked to the extensive axonal growth that occurs during development [5]. It has been shown that not long after birth, cAMP levels in dorsal root ganglia (DRG) neurons rapidly decline in parallel with the reduced regenerative capacity of their CNS axons [5], [21]. Similarly, blocking protein kinase A (PKA), a downstream effector of cAMP, using the PKA antagonists KT5720 and Rp-cAMPS in cultured rat DRG and retinal ganglion (RG) neurons resulted
Neurotrophins and cAMP
Neurotrophins are important signalling molecules for cell survival and neurite outgrowth. They can promote axon growth even in adult neurons exposed to myelin-associated inhibitors. For example, cerebellar and DRG neurons plated with the neurotrophins BDNF or neurite growth factor (NGF) prior to exposure to MAG and/or myelin, have increased neurite outgrowth compared to neurons without neurotrophins [22]. Dougherty et al. [23] further explored neurotrophin expression in the spinal cord and
Elevating cAMP levels to promote neurite outgrowth
With the knowledge that elevated cAMP levels could promote neurite outgrowth in the inhibitory environment of the injured adult mammalian CNS, it was a logical next step to target cAMP and other parts of its signalling pathway to promote regeneration. Neumann and colleagues [36] demonstrated the pro-regenerative effect of high cAMP levels by injecting a cAMP analog (db-cAMP) in DRGs in vivo, thus activating downstream effectors including PKA, and CREB (see Fig. 1) and promoting regeneration of
Raising cAMP using electrical stimulation
The importance of cAMP in the regulation of neurite outgrowth and myelin-associated inhibition is illustrated even further by the finding that cAMP levels drop in the spinal cord, brainstem, and cortex following SCI [39], consistent with lack of axonal regeneration. A possible reason for the post injury decline in cAMP is the disuse of affected limbs and the associated inactivity of neurons within the involved circuitry. This is supported by the finding that directly following unilateral SCI in
cAMP signalling
High neuronal cAMP levels are linked to increased neurite outgrowth in both permissive and inhibitory environments, but the mechanisms by which cAMP increases neuronal growth have yet to be fully understood. A well-known downstream effector of cAMP is PKA (Fig. 1). Various studies have shown that blocking PKA using KT5720 eliminates the growth promoting effects of increased cAMP levels [5], [12], [17], [37], [54], [55] (Fig. 1). Qiu et al. [37], showed that there are two phases of regeneration,
Exchange protein activated by cAMP
EPAC is activated by cAMP independently of PKA (Fig. 1) and likely a key factor in cAMP induced neurite outgrowth, as well as many other aspects of cAMP signalling in other areas of the body that had been previously thought to be the result of PKA activation [64]. Two isoforms have been described, EPAC1 and EPAC2, with varying expression levels and tissue distributions throughout development [65]. EPAC1 is highly expressed in embryonic nerve cells while EPAC2 is expressed mostly in developed
Conclusion
Numerous studies suggest that increasing cAMP levels can increase neurite outgrowth and could be effective as both short and long-term treatment option for SCI. However, due to cAMP being an important and ubiquitous signalling molecule throughout the body, direct activation of cAMP would likely cause numerous adverse side effects. Thus, the understanding of how to specifically activate downstream targets is an important step in the development of clinically relevant treatments. As more accurate
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