Epac2 Elevation Reverses Inhibition by Chondroitin Sulfate Proteoglycans In Vitro and Transforms Postlesion Inhibitory Environment to Promote Axonal Outgrowth in an Ex Vivo Model of Spinal Cord Injury

The Journal of Neuroscience, 2019 · DOI: https://doi.org/10.1523/JNEUROSCI.0374-19.2019 · Published: October 16, 2019

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This research investigates a new approach to spinal cord injury (SCI) treatment by focusing on Epac2, a protein that promotes nerve cell growth. The study found that activating Epac2 can help nerve cells grow even when surrounded by substances that normally stop their growth. The researchers used a special gel to deliver an Epac2 activator to the injured spinal cord in a lab model, which led to improved nerve fiber growth across the injury site and reduced inflammation. This suggests a potential new way to encourage spinal cord repair. In rats with spinal cord injuries, treatment with the Epac2-activating gel resulted in better movement abilities for several weeks after the treatment. This indicates that targeting Epac2 could be a promising strategy for SCI treatment.

Study Duration

Not specified

Participants

Male adult Wistar rats weighing between 180 and 200 g

Evidence Level

Level III, ex vivo and in vivo experimental study

Key Findings

1
Epac2 activation significantly enhanced neurite outgrowth of postnatal rat cortical neurons and markedly overcame the inhibition by chondroitin sulfate proteoglycans and mature astrocytes on neuron growth in vitro.
2
Epac2 activation profoundly modulated the lesion environment by reducing astrocyte/microglial activation and transforming astrocytes into elongated morphology that guided outgrowing axons in an ex vivo model of SCI.
3
Delivery of an Epac2 agonist via a self-assembling hydrogel resulted in significantly better locomotor performance for up to 4 weeks after treatment in male adult rats with contusion SCI.

Research Summary

This study demonstrates that activating Epac2, a downstream effector of cAMP, enhances neurite outgrowth in vitro, even in an inhibitory environment. Using a novel biomaterial-based drug delivery system, specific activation of Epac2 enhances axonal outgrowth and minimizes glial activation in an ex vivo model of spinal cord injury. The findings suggest a new strategy for spinal cord repair by promoting axonal regeneration and modulating the inhibitory environment after injury.

Practical Implications

Therapeutic Potential for SCI

S-220, an Epac2 agonist, shows promise as a therapeutic agent for SCI due to its beneficial effects on neurons and glia, facilitating axonal outgrowth.

Novel Drug Delivery System

The study highlights the potential of self-assembling Fmoc-based hydrogels as a minimally invasive drug delivery system for sustained and local release of therapeutics in SCI.

Modulation of Glial Environment

Epac2 activation can transform the inhibitory post-SCI environment by reducing astrocyte/microglial activation and promoting an astrocyte morphology that supports axonal guidance.

Study Limitations

1
Further in vivo immunohistochemical and functional studies are required to validate the potential of these treatments in SCI.
2
Future studies also need to further optimize the injected hydrogel volume and S-220 dose and establish the in vivo effects of S-220 on axonal outgrowth and glial activation.
3
Caution is needed when extrapolating our strategy to other CNS injuries, such as brain injury and stroke

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