The therapeutic potential of targeting exchange protein directly activated by cyclic adenosine 3′,5′-monophosphate (Epac) for central nervous system trauma

Neural Regeneration Research, 2021 · DOI: https://doi.org/10.4103/1673-5374.293256 · Published: September 22, 2020

Spinal Cord Injury Regenerative Medicine Immunology

Simple Explanation

Traumatic spinal cord injury (TSCI) affects millions worldwide, often leading to permanent disability due to damage and subsequent events like inflammation and glial scar formation. Cyclic adenosine 3′,5′-monophosphate (cAMP) plays important roles in the central nervous system, and increasing its levels has shown promise in improving axonal regeneration after TSCI in animal models. Targeting Epac2, a downstream effector of cAMP mainly expressed in the adult central nervous system, could be a novel strategy for TSCI repair by modulating the post-lesion environment.

Study Duration

Not specified

Participants

Animal models

Evidence Level

Review

Key Findings

1
Epac2 activation can modulate the post-lesion environment following traumatic spinal cord injury, decreasing the activation of astrocytes and microglia.
2
Pilot data suggest that Epac2 activation can lead to functional improvement in in vivo models of traumatic spinal cord injury.
3
Epac2 mediates positive turning behaviors in growing axons, suggesting it plays a role in axonal guidance during neural development.

Research Summary

This review discusses the potential of targeting Epac2, a downstream effector of cAMP, as a therapeutic strategy for traumatic spinal cord injury (TSCI). Epac2 is mainly expressed postnatally in the CNS and mediates positive effects of cAMP on neuronal growth and guidance and can also modulate microglial/astrocyte activation. Further investigation of Epac/Rap1 is essential to reveal the mechanisms that lead to the modulation of the inhibitory environment and axonal regeneration.

Practical Implications

Therapeutic Target

Epac2 represents a promising target for manipulating the outcome of TSCI due to its role in neuronal growth, guidance, and modulation of glial cell activation.

CNS-Specific Effects

Epac2 expression is largely limited to the adult CNS, offering the potential for CNS tissue-specific effects and reduced side effects compared to treatments that manipulate cAMP levels directly.

Combination Therapies

Combining Epac2-targeted therapies with other strategies, such as locomotor training, could maximize functional recovery after TSCI.

Study Limitations

1
Direct modulation of cAMP signalling is unlikely to find a use in the clinic due to the ubiquity of the cAMP pathways in humans.
2
Further investigation of the molecular events downstream of Epac/Rap1 is essential to reveal the mechanisms that lead to the modulation of the inhibitory environment and axonal regeneration.
3
The review primarily focuses on animal models, and further research is needed to confirm the therapeutic potential of Epac2 in human TSCI patients.

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