Abstract
Spinal cord injury (SCI) results in multiple pathophysiological processes, including blood–spinal cord barrier disruption, hemorrhage/ischemia, oxidative stress, neuroinflammation, scar formation, and demyelination. These responses eventually lead to severe tissue destruction and an inhibitory environment for neural regeneration.cAMP signaling is vital for neurite outgrowth and axonal guidance. Stimulating intracellular cAMP activity significantly promotes neuronal survival and axonal regrowth after SCI.However, neuronal cAMP levels in adult CNS are relatively low and will further decrease after injury. Targeting cAMP signaling has become a promising strategy for neural regeneration over the past two decades. Furthermore, studies have revealed that cAMP signaling is involved in the regulation of glial cell function in the microenvironment of SCI, including macrophages/microglia, reactive astrocytes, and oligodendrocytes. cAMP-elevating agents in the post-injury milieu increase the cAMP levels in both neurons and glial cells and facilitate injury repair through the interplay between neurons and glial cells and ultimately contribute to better morphological and functional outcomes. In recent years, combination treatments associated with cAMP signaling have been shown to exert synergistic effects on the recovery of SCI. Agents carried by nanoparticles exhibit increased water solubility and capacity to cross the blood–spinal cord barrier. Implanted bioscaffolds and injected hydrogels are potential carriers to release agents locally to avoid systemic side effects. Cell transplantation may provide permissive matrices to synergize with the cAMP-enhanced growth capacity of neurons. cAMP can also induce the oriented differentiation of transplanted neural stem/progenitor cells into neurons and increase the survival rate of cell grafts. Emerging progress focused on cAMP compartmentation provides researchers with new perspectives to understand the complexity of downstream signaling, which may facilitate the clinical translation of strategies targeting cAMP signaling for SCI repair.
Highlights
Spinal cord injury (SCI) is a devastating neural trauma with an incidence of 54 patients per million people in the United States (Frontera and Mollett, 2017)
In the classic mammalian model, extracellular stimuli bind to GPCRs on the cell membrane and initiate a cascade of biochemical reactions, including the activation of tmACs, which catalyze the conversion of ATP to cAMP. cAMP diffuses throughout the cell and activates its downstream effectors
This compartment is organized by the scaffold protein mAKAPα (AKAP6α), and the activation of mAKAPα-associated cAMP signaling increases retinal ganglion cell survival after injury both in vitro and in vivo (Boczek et al, 2019)
Summary
Spinal cord injury (SCI) is a devastating neural trauma with an incidence of 54 patients per million people in the United States (Frontera and Mollett, 2017). CAMP has been shown to regulate the function of glial cells and interact in complex ways with other signals generated by SCI, including macrophage/microglia polarization, astrocyte activation, and oligodendrocyte differentiation. Combination treatments can exert synergistic effects on attenuating inflammation, reducing cell death, minimizing the size of the lesion cavity, inhibiting CSPGs expression, promoting axon regeneration, and eventually leading to better functional recovery. The literature review described above revealed that cAMP-elevating agents increase the cAMP levels in both neurons and glial cells and exert protective effects to promote tissue repair after SCI. During the acute and subacute phase of SCI, cAMP regulates the functions of macrophages/microglia and RAs to attenuate local inflammation, reduce the apoptosis of neurons and oligodendrocytes, and inhibit glial scar formation and demyelination.
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