{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:04:30Z","timestamp":1785423870751,"version":"3.56.0"},"reference-count":98,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Inonu University Scientific Research Projects Coordination Unit","award":["2016\/169"],"award-info":[{"award-number":["2016\/169"]}]},{"award":["2016\/169"],"award-info":[{"award-number":["2016\/169"]}],"id":[{"id":"https:\/\/ror.org\/04asck240","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatic ischemia\u2013reperfusion injury (IRI) is a major cause of liver damage and is characterized by oxidative stress, inflammatory signaling, and hepatocellular apoptosis. Aim: This study investigated the hepatoprotective effects of agomelatine (AGO) administered before ischemia or at the onset of reperfusion in a hepatic IRI model. Rats were allocated into four experimental groups: Sham, IRI, IRI+AGO, and AGO+IRI. Hepatic ischemia was induced by clamping the hepatic pedicle for 1 h followed by 1 h of reperfusion. AGO (20 mg\/kg) was administered orally either before ischemia or at the onset of reperfusion. Oxidative stress markers, antioxidant enzymes, nitric-oxide-related parameters, cytokines, liver injury enzymes, and histopathological changes were evaluated. IRI increased oxidant markers and reduced antioxidant defenses. AGO treatment improved redox balance and antioxidant parameters in both treatment groups, with stronger antioxidant responses observed in the AGO+IRI group. Nitric oxide (NO)-related markers differed among groups, including changes in L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) levels, and interleukin-6 (IL-6) levels decreased following AGO administration, particularly in the AGO+IRI group. Histopathological injury and caspase-3 expression were also attenuated in AGO-treated animals. AGO attenuates hepatic IRI by improving redox balance, modulating NO metabolism, and reducing IL-6\u2013associated signaling and apoptosis, with stronger protection when administered before ischemia.<\/jats:p>","DOI":"10.3390\/ijms27073246","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T15:14:43Z","timestamp":1775142883000},"page":"3246","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cytoprotective Effects of Agomelatine on Hepatic Ischemia\u2013Reperfusion Injury in a Rat Model"],"prefix":"10.3390","volume":"27","author":[{"given":"Yilmaz","family":"Bilgic","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6864-7711","authenticated-orcid":false,"given":"Sami","family":"Akbulut","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oguzhan","family":"Yildirim","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9018-7849","authenticated-orcid":false,"given":"Onural","family":"Ozhan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5686-7867","authenticated-orcid":false,"given":"Azibe","family":"Yildiz","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Erdemli","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet Erman","family":"Erdemli","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-1243","authenticated-orcid":false,"given":"Adem","family":"Kose","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigar","family":"Vardi","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5401-0720","authenticated-orcid":false,"given":"Yusuf","family":"Turkoz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9497-3468","authenticated-orcid":false,"given":"Hakan","family":"Parlakpinar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Inonu University, 44280 Malatya, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion\u2014From mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat. 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