{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:57:51Z","timestamp":1792497471675,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81903590"],"award-info":[{"award-number":["81903590"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U22A20272"],"award-info":[{"award-number":["U22A20272"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Natural Science Foundation of China Regional Innovation and Development Joint Fund","award":["81903590"],"award-info":[{"award-number":["81903590"]}]},{"name":"National Natural Science Foundation of China Regional Innovation and Development Joint Fund","award":["U22A20272"],"award-info":[{"award-number":["U22A20272"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Stroke is one of the leading causes of death. (D-ala2, D-leu5) enkephalin (DADLE) is a synthetic peptide and highly selective delta opioid receptor (\u03b4OR) agonist that has exhibited protective properties in ischemia. However, the specific target and mechanism are still unclear. The present study explores the expression of \u03b4OR on brain microvascular endothelial cells (BMECs) and whether DADLE could relieve I\/R-induced injury by reducing apoptosis. A lateral ventricular injection of DADLE for pretreatment, the neurofunctional behavior score, and TTC staining, were used to evaluate the protective effect of DADLE. Immunofluorescence technology was used to label different types of cells with apoptosis-positive signals to test co-localization status. Primary cultured BMECs were separated and treated with DADLE, accompanied by OGD\/R. The CCK-8 test was conducted to evaluate cell viability and TdT-mediated dUTP Nick-end Labelling (TUNEL) staining to test apoptosis levels. The levels of apoptosis-related proteins were analyzed by Western blotting. The co-localization results showed that BMECs, but not astrocytes, microglia, or neurons, presented mostly TUNEL-positive signals, especially in the Dentate gyrus (DG) area of the hippocampus. Either activation of \u03b4ORs on rats\u2019 brains or primary BMECs mainly reduce cellular apoptosis and relieve the injury. Interference with the expression \u03b4OR could block this effect. DADLE also significantly increased levels of Bcl-2 and reduced levels of Bax. \u03b4OR\u2019s expressions can be detected on the BMECs, but not on the HEK293 cells, by Western blotting and IFC. Therefore, DADLE exerts a cytoprotective effect, primarily under hypoxia-ischemic injury\/reperfusion conditions, by targeting BMECs to inhibit apoptosis.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010046","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:26:25Z","timestamp":1671765985000},"page":"46","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Delta Opioid Peptide Targets Brain Microvascular Endothelial Cells Reducing Apoptosis to Relieve Hypoxia-Ischemic\/Reperfusion Injury"],"prefix":"10.3390","volume":"15","author":[{"given":"Ran","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongfang","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingchao","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7263-4748","authenticated-orcid":false,"given":"Bing","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesha","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0140-6736(16)30962-X","article-title":"Stroke","volume":"389","author":"Hankey","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Boldsen, J.K., Engedal, T.S., Pedraza, S., Cho, T.-H., Thomalla, G., Nighoghossian, N., Baron, J.-C., Fiehler, J., \u00d8stergaard, L., and Mouridsen, K. 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