{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:07:10Z","timestamp":1790928430742,"version":"4.1.0"},"reference-count":75,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"Turkish Scientific Research Council (TUBITAK)","doi-asserted-by":"publisher","award":["119S769"],"award-info":[{"award-number":["119S769"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004410","name":"Turkish Scientific Research Council (TUBITAK)","doi-asserted-by":"publisher","award":["#1919B012301772"],"award-info":[{"award-number":["#1919B012301772"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Hydrogen sulfide (H2S) is an endogenously produced gaseous neurotransmitter. H2S donors exhibited neuroprotection in oxidative-stress-related disorders in preclinical studies, but odor and short half-lives have limited their clinical use. However, endogenous H2S stimulators with antioxidant properties have advantages over H2S donors regarding safety and patient compliance. Empagliflozin (EMPA), a sodium\u2013glucose cotransporter-2 (SGLT2) inhibitor widely used in the treatment of diabetes mellitus (DM), exerted similar neuroprotective and antioxidant effects as H2S and shares common mechanisms. This study aimed to investigate the role of H2S in the antioxidant effects of EMPA in the brain. Methods: The effects of EMPA on H2S production and reactive oxygen species (ROS) formation were assessed ex vivo in mouse brain under normal conditions and pyrogallol-induced oxidative stress. Moreover, rats were divided into the following four groups: nondiabetic, EMPA-treated nondiabetic, streptozotocin (STZ)-induced diabetic, and EMPA-treated, STZ-induced diabetic. Endogenous H2S and ROS levels in the brain were measured using methylene blue and chemiluminescence assays, respectively. Results: Ex vivo EMPA treatment significantly increased endogenous H2S formation in both healthy and pyrogallol-induced oxidative stress, as well as reduced ROS formation in mouse brain; these effects were significantly reversed by the H2S synthesis inhibitor aminooxyacetic acid (AOAA). Oral EMPA administration significantly elevated brain H2S levels in both nondiabetic and diabetic rats and reduced ROS formation. These effects were inhibited by AOAA. Conclusions: Our study revealed a novel mechanism by which EMPA can reduce oxidative stress in neurodegenerative disorders by triggering H2S synthesis in the brain.<\/jats:p>","DOI":"10.3390\/ph18091259","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T06:08:37Z","timestamp":1756102117000},"page":"1259","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Empagliflozin Protects Against Oxidative Stress in the Diabetic Brain by Inducing H2S Formation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3934-3479","authenticated-orcid":false,"given":"Emine Nur","family":"Ozbek","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir 35040, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5659-8839","authenticated-orcid":false,"given":"Zeynep Elif","family":"Yesilyurt Dirican","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara 06330, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medine","family":"Makal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir 35040, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebru","family":"Arioglu Inan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara 06560, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7788-1657","authenticated-orcid":false,"given":"Gunay","family":"Yetik-Anacak","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.2337\/dc14-S081","article-title":"Diagnosis and classification of diabetes mellitus","volume":"37","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Caturano, A., Rocco, M., Tagliaferri, G., Piacevole, A., Nilo, D., Di Lorenzo, G., Iadicicco, I., Donnarumma, M., Galiero, R., and Acierno, C. 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