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However, its role in ischemic stroke (IS), which is a leading cause of disability and death worldwide and has limited therapeutic options, is uncertain. The aim of the present study was to investigate the beneficial effects of ELA on neuron survival after ischemia and the underlying molecular mechanisms. Primary cortical neurons were isolated from the cerebral cortex of pregnant C57BL\/6J mice. Flow cytometry and immunofluorescence showed that ELA inhibited oxygen\u2013glucose deprivation\u00a0(OGD)\u00a0-induced apoptosis and axonal damage in vitro. Additionally, analysis of the Gene Expression Omnibus database revealed that the expression of microRNA-124-3p (miR-124-3p) was decreased in blood samples from patients with IS, while the expression of C-terminal domain small phosphatase 1 (CTDSP1) was increased.\u00a0These results indicated that miR-124-3p and CTDSP1 were related to ischemic stroke, and there might be a negative regulatory relationship between them. Then, we found that ELA significantly elevated miR-124-3p expression, suppressed CTDSP1 expression, and increased p-AKT expression by binding to the APJ receptor under OGD\u00a0in vitro. A dual-luciferase reporter assay confirmed that CTDSP1 was a direct target of miR-124-3p. Furthermore, adenovirus-mediated overexpression of CTDSP1 exacerbated neuronal apoptosis and axonal damage and suppressed AKT phosphorylation, while treatment with ELA or miR-124-3p mimics reversed these effects. In conclusion, these results indicated that ELA could alleviate neuronal apoptosis and axonal damage by upregulating miR-124-3p and activating the CTDSP1\/AKT signaling pathway. This study, for the first time, verified the protective effect of ELA against neuronal injury after ischemia and revealed the underlying mechanisms. We demonstrated the potential for the use of ELA as a therapeutic agent in the treatment of ischemic stroke.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10571-023-01352-6","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T17:01:59Z","timestamp":1682614919000},"page":"2989-3003","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Elabela, a Novel Peptide, Exerts Neuroprotective Effects Against Ischemic Stroke Through the APJ\/miR-124-3p\/CTDSP1\/AKT Pathway"],"prefix":"10.1007","volume":"43","author":[{"given":"Kang-long","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuang-mei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-yu","family":"Hou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-hui","family":"Hong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu-xiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-qing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guang-hui","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao-tao","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-dong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-ying","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"key":"1352_CR1","doi-asserted-by":"publisher","first-page":"16851","DOI":"10.1074\/jbc.RA118.004722","volume":"293","author":"NT Burkholder","year":"2018","unstructured":"Burkholder NT, Mayfield JE, Yu X, Irani S, Arce DK, Jiang F, Matthews WL, Xue Y, Zhang YJ (2018) Phosphatase activity of small C-terminal domain phosphatase 1 (SCP1) controls the stability of the key neuronal regulator RE1-silencing transcription factor (REST). 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