Investigating the Effects of Epac2 Activation in an In Vitro Cortical Mechanical Injury Model for Central Nervous System Repair

TL;DR

This study explores how activating Epac2 with S-220 promotes CNS repair by protecting neurons and reducing harmful inflammation after injury.

Contribution

The study introduces a novel in vitro model to assess Epac2's role in CNS repair across multiple cell types.

Findings

Epac2 activation with S-220 protects neurons and oligodendrocytes after injury.

S-220 reduces astrogliosis and microgliosis, promoting axonal outgrowth.

The findings suggest Epac2 elevation is a promising strategy for CNS repair.

Abstract

Globally, around 21 million people are currently living with a spinal cord injury (SCI), which causes loss of neural function and has no cure, creating substantial social and economic challenges. Several factors impede central nervous system (CNS) repair, including the limited intrinsic regenerative capacity of adult mammalian central nervous system neurons, the formation of cavities and glial scars, and the presence of inhibitory molecules at the injury site. Studies in an ex vivo SCI model suggest that exchange protein directly activated by cAMP 2 (Epac2) elevation by the agonist S‐220 can transform a post‐lesion inhibitory environment to one, which promotes axonal outgrowth. However, this ex vivo preparation did not allow the detailed and accurate assessment of responses of individual cell populations following injury. Moreover, it was unclear if S‐220 conferred neuroprotection in the ex vivo model. To address these issues, here we use a relatively novel but simple in vitro model of CNS injury to further examine the effects of S‐220 on all key CNS cell populations, as it included neurons, oligodendrocytes, astrocytes, microglia, and oligodendrocyte precursor cells. The results show that following S‐220 treatment, Epac2 activation conferred neuroprotection to neurons and oligodendrocytes following the in vitro injury. It also produced a permissive postinjury environment by reducing astrogliosis and microgliosis, which resulted in increased axonal outgrowth into the injury gap. Our data therefore suggest that elevating Epac2 is a novel repair strategy for CNS injury.

Study design. An in vitro cortical mechanical injury model for central nervous system repair, which contained five major neural tissue cells, is established from rats. After 7 days in vitro, the injuries are introduced, and Epac2 agonist S‐220 treatments are applied immediately after injury. The results suggest that Epac2 activation is a novel repair strategy for CNS repair.

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