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

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.