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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\u00a0vivo SCI model suggest that exchange protein directly activated by cAMP 2 (Epac2) elevation by the agonist S\u2010220 can transform a post\u2010lesion inhibitory environment to one, which promotes axonal outgrowth. However, this ex\u00a0vivo preparation did not allow the detailed and accurate assessment of responses of individual cell populations following injury. Moreover, it was unclear if S\u2010220 conferred neuroprotection in the ex\u00a0vivo model. To address these issues, here we use a relatively novel but simple in\u00a0vitro model of CNS injury to further examine the effects of S\u2010220 on all key CNS cell populations, as it included neurons, oligodendrocytes, astrocytes, microglia, and oligodendrocyte precursor cells. The results show that following S\u2010220 treatment, Epac2 activation conferred neuroprotection to neurons and oligodendrocytes following the in\u00a0vitro 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.<\/jats:p>","DOI":"10.1111\/ejn.70286","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T16:10:32Z","timestamp":1761408632000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating the Effects of Epac2 Activation in an In\u00a0Vitro Cortical Mechanical Injury Model for Central Nervous System Repair"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9664-000X","authenticated-orcid":false,"given":"Hongming","family":"Ma","sequence":"first","affiliation":[{"name":"Institute of Medical Sciences, School of Medicine, Medical Sciences &amp; Nutrition University of Aberdeen  Aberdeen Scotland 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