The combination of db-cAMP and ChABC with poly(propylene carbonate) microfibers promote axonal regenerative sprouting and functional recovery after spinal cord hemisection injury

Xia, Tongliang; Huang, Bin; Ni, Shilei; Gao, Lei; Wang, Jiangang; Wang, Jian; Chen, Anjing; Zhu, Shirley; Wang, Benlin; Li, Gang; Zhu, Shuchai; Li, Xingang

doi:10.1016/j.biopha.2016.12.045

Cited by 19 publications

(11 citation statements)

References 47 publications

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“…Because cAMP exerts immunosuppressive effects on inflammatory cells, the combination of cAMP-elevating agents and bioscaffolds may not only specifically deliver drugs to the lesion site but also attenuate local inflammation. Previous studies have shown that db-cAMP delivered by poly (propylene carbonate) microfibers and collagen scaffolds released to the lesion site sustainably and significantly promotes injury repair (Xia et al, 2013(Xia et al, , 2017Li et al, 2016). Hydrogels have microporous structures that closely match the extracellular matrix of the spinal cord, and drugs loaded in hydrogels release more efficiently and durably at the lesion site.…”

Section: Kim Et Al (2011)mentioning

confidence: 99%

Multifaceted Roles of cAMP Signaling in the Repair Process of Spinal Cord Injury and Related Combination Treatments

Zhou

Wang

Han

et al. 2022

Front. Mol. Neurosci.

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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.

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Section: Kim Et Al (2011)mentioning

confidence: 99%

Multifaceted Roles of cAMP Signaling in the Repair Process of Spinal Cord Injury and Related Combination Treatments

Zhou

Wang

Han

et al. 2022

Front. Mol. Neurosci.

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“…Important axonal regenerative sprouting was also observed within the glial scars, as well as significant inhibition of glial scar formation. PPC modified microfibers provided significant motor function recovery, showing that the sustained co-delivery of db-cAMP and ChABC from polymeric matrices represents a promising strategy for CNS-related regenerative applications [129].…”

Section: Nanomaterials For Central Nervous System Regenerative Appmentioning

confidence: 99%

Nanomaterial-Based Approaches for Neural Regeneration

Teleanu

Gherasim

Gherasim³

et al. 2019

Pharmaceutics

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Mechanical, thermal, chemical, or ischemic injury of the central or peripheral nervous system results in neuron loss, neurite damage, and/or neuronal dysfunction, almost always accompanied by sensorimotor impairment which alters the patient’s life quality. The regenerative strategies for the injured nervous system are currently limited and mainly allow partial functional recovery, so it is necessary to develop new and effective approaches for nervous tissue regenerative therapy. Nanomaterials based on inorganic or organic and composite or hybrid compounds with tunable physicochemical properties and functionality proved beneficial for the transport and delivery/release of various neuroregenerative-relevant biomolecules or cells. Within the following paragraphs, we will emphasize that nanomaterial-based strategies (including nanosized and nanostructured biomaterials) represent a promising alternative towards repairing and regenerating the injured nervous system.

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“…To date, cAMP-targeted SCI treatments have focused on the application of general modulators of the pathway, such as adenylate cyclase (AC) stimulators, phosphodiesterase (PDE) inhibitors [ 25 , 26 ], or cAMP analogues [ 27 ] alone or in combination with cell therapies [ 20 , 28 – 30 ]. While many of these studies reported functional recovery, applying more specific drugs may provide a deeper understanding of the individual implications of EPAC2/PKA in driving regeneration in the context of SCI and NPC transplantation.…”

Section: Introductionmentioning

confidence: 99%

NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation

Martínez-Rojas

Giraldo

Grillo-Risco

et al. 2022

Cell. Mol. Life Sci.

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Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, which persists from early subacute to chronic stages of SCI and affects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the significant downregulation of cAMP signalling components immediately after SCI, involving genes such as EPAC2 (exchange protein directly activated by cAMP), PKA, BDNF, and CAMKK2. The ectopic transplantation of spinal cord-derived NPCs at acute or subacute stages of SCI induces a significant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-affected genes. The transcriptional modulation pattern driven by NPC transplantation includes the rescued expression of cAMP signalling genes, including EPAC2. We also explore how the sustained in vivo inhibition of EPAC2 downstream signalling via the intrathecal administration of ESI-05 for 1 week impacts therapeutic mechanisms involved in the NPC-mediated treatment of SCI. NPC transplantation in SCI rats in the presence and absence of ESI-05 administration prompts increased rostral cAMP levels; however, NPC and ESI-05 treated animals exhibit a significant reduction in EPAC2 mRNA levels compared to animals receiving only NPCs treatment. Compared with transplanted animals, NPCs + ESI-05 treatment increases the scar area (as shown by GFAP staining), polarizes microglia into an inflammatory phenotype, and increases the magnitude of the gap between NeuN + cells across the lesion. Overall, our results indicate that the NPC-associated therapeutic mechanisms in the context of SCI involve the cAMP pathway, which reduces inflammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism. Graphical abstract

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The combination of db-cAMP and ChABC with poly(propylene carbonate) microfibers promote axonal regenerative sprouting and functional recovery after spinal cord hemisection injury

Cited by 19 publications

References 47 publications

Multifaceted Roles of cAMP Signaling in the Repair Process of Spinal Cord Injury and Related Combination Treatments

Multifaceted Roles of cAMP Signaling in the Repair Process of Spinal Cord Injury and Related Combination Treatments

Nanomaterial-Based Approaches for Neural Regeneration

NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation

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