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Older people are more vulnerable to the adverse effects of antidepressants than the young. Therefore, creating antidepressants from medicinal herbs that are more effective and safer is inevitable. <jats:italic>Ginkgo biloba<\/jats:italic> L. leaf extract (EGb761) is broadly applied for treating various neuronal dysfunctions. The present study aimed to evaluate the ameliorative and antidepressant effects of EGb761 against reserpine (RES)-induced depression like symptoms and associated comorbidities in aged female rats. Besides, it compared its efficacy with the antidepressant duloxetine (DULX), offering a more comprehensive understanding of therapeutic potential of EGb 761. Rats grouped into control group, EGb 761-H group, RES group, RES plus either EGb 761-L, EGb 761-H, or DULX groups. The antidepressant effects of EGb 761 were evaluated through a series of behavioral tests, measurement of depression biochemical markers, performing neuronal histopathology and immunohistochemical analyses. EGb 761 significantly attenuated behavioral deficits in the open field test and reduced immobility time in the forced swimming test. Moreover, EGb 761 exerted antidepressant-like actions by ameliorating neurotransmitter imbalances, restoring redox homeostasis in cortical region. Also, EGb 761 increased level of ATP, diminished DNA fragmentation, decreased caspase-3 immunoreactivity and increased immunoreactivity of synaptophysin in the cerebral cortex, besides it enhanced the histological architecture of this region. Overall, EGb 761 has the potential effects to manage LLD focus on the role of both serotonergic and noradrenergic systems in mediating these effects, alongside the impact on oxidative\/nitrosative stress.<\/jats:p>","DOI":"10.1007\/s00210-025-03972-9","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T06:11:11Z","timestamp":1742278271000},"page":"12115-12131","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ginkgo biloba L. leaf extract (EGb 761) alleviates reserpine-induced depression-like symptoms in aged rats by enhancing serotonin\/norepinephrine levels and reducing oxidative\/nitrosative stress"],"prefix":"10.1007","volume":"398","author":[{"given":"Dina H.","family":"Ali","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda G.","family":"Hegazy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham H. 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