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Sodium glucose co-transporter 2 receptors (SGLT2) have been found in various brain regions, suggesting the potential neuroprotective properties of SGLT2 inhibitors as dapagliflozin (DGF). This study aimed to investigate the effect of DGF on behavioral, and neurodegenerative changes in chronic restraint stress (CRS) as an animal model of cognitive impairment. Forty-eight male rats were allocated into four groups:\n                    <jats:italic>Control<\/jats:italic>\n                    ;\n                    <jats:italic>CRS-subjected group<\/jats:italic>\n                    , rats were subjected to chronic restraint stress for 6 weeks to induce cognitive impairment;\n                    <jats:italic>DGF-treated CRS group<\/jats:italic>\n                    , dapagliflozin was given daily by oral gavage; and\n                    <jats:italic>DGF-administered group<\/jats:italic>\n                    . Behavioral tests were performed and fasting serum glucose, insulin, and corticosterone levels were measured\n                    <jats:italic>.<\/jats:italic>\n                    Hippocampal oxidative markers, insulin signaling, mitochondrial function, amyloid beta, p-tau, and brain-derived neurotrophic factor (BDNF) gene expression were evaluated. DGF significantly prevented CRS-induced cognitive dysfunction (Y maze and Morris water maze tests). Also, DGF ameliorated hippocampal neurodegenerative changes by decreasing tau and amyloid beta levels, while increasing BDNF gene expression. DGF reduced hippocampal phosphorylated mammalian target of rapamycin (p-mTOR) and protein kinase B (p-Akt) levels. In addition to its antioxidant effects, DGF increased ATP levels and cytochrome C oxidase activity. These findings were confirmed by transmission electron microscopic (TEM) examination. The current study demonstrates a biological link between chronic stress, insulin resistance, and cognitive impairment. Dapagliflozin has therapeutic potential in alleviating cognitive deficits and neurodegeneration primarily due to its insulin-sensitizing and antioxidant properties, along with its capacity to enhance mitochondrial function.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-04136-5","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T05:42:23Z","timestamp":1747806143000},"page":"15837-15855","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dapagliflozin mitigates cognitive deficits in a rat model of chronic restrained stress by addressing insulin resistance and mitochondrial dysfunction"],"prefix":"10.1007","volume":"398","author":[{"given":"Nourhan M.","family":"Gamal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam El","family":"Bakly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherin S. 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