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With recent pharmacological studies showing the potential antidepressant properties of X. americana extract, this study aimed to evaluate the antidepressant-like effects of the compound(s) isolated from X. americana extract using the forced swim test (FST) and tail suspension test (TST) models predictive of depression. The extracts, administered orally within a dose range of 100\u2013400\u2009mg\/kg, notably decreased the immobility time in both the FST and the TST. The most significant reduction occurred at the highest dose of 400\u2009mg\/kg, with a decrease of 117.66\u2009s in FST and 53.5\u2009s in TST. However, this reduction in immobility was not linked to changes in movements, as observed in an open-field test (OFT), suggesting that the effect of the extracts was not due to activation of locomotion. Subsequently, a sesquiterpene lactone, dehydrocostus lactone (1) was isolated through solubility-based fractionation and column chromatography of the active root bark extract of X. americana. Dehydrocostus lactone (400\u2009mg\/kg) demonstrated a 46.50\u2009s reduction in immobility time in the FST, which was comparable to the positive control, imipramine (30\u2009mg\/kg). With a highly favorable docking score of \u22128.365\u2009kcal\/mol on an antidepressant target, monoamine oxidase A (MAO-A; pdb ID: 2BXS), dehydrocostus lactone (1) potentially outperforms the standard MAO-A inhibitor drug, isocarboxazid (\u22125.847\u2009kcal\/mol). Dehydrocostus lactone (1) displayed strong interactions involving hydrogen bond and hydrophobic and electrostatic interactions with specific MAO-A binding site residues. These findings highlight that the antidepressant-like activity of X. americana is partly attributed to the presence of dehydrocostus lactone. Additionally, it also supports the traditional medicinal use of the plant for treating depression.<\/jats:p>","DOI":"10.1155\/2024\/6680821","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T16:20:05Z","timestamp":1706977205000},"page":"1-10","source":"Crossref","is-referenced-by-count":7,"title":["Antidepressant-Like Activity and Molecular Docking Analysis of a Sesquiterpene Lactone Isolated from the Root Bark of Ximenia americana (L.)"],"prefix":"10.1155","volume":"2024","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5034-7107","authenticated-orcid":true,"given":"Tekeste","family":"Abebe","sequence":"first","affiliation":[{"name":"Pharmacy School, College of Health Sciences and Medicine, Wolaita Sodo University, P.O. 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