{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:30:24Z","timestamp":1787146224088,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: Traditional antidepressants are associated with undesirable side effects, limited efficacy, and delayed therapeutic responses. Natural products have emerged as a potential alternative to these drugs. This research aimed to investigate the antidepressant-like activity and possible mechanism of Orthosiphon stamineus (OS) leaf ethanolic extract. Methods: Molecular docking and in vitro studies were performed to assess the inhibitory activity of ethanolic extracts of OS leaves against the monoamine oxidase (MAO-A) enzyme. Behavioral tests were used to evaluate the antidepressant-like activity of the 95% ethanol extract in reserpine-treated rats, followed by histopathological examination and measurement of hippocampal serotonin (5-HT), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF). Results: The main active compounds, particularly rosmarinic acid and eupatorin, exhibited favorable binding affinities to the MAO-A active site. The 95% and 50% ethanol extracts of OS showed dose-dependent MAO-A inhibitory activity with ICs50 of 88.67 and 103.2 \u00b5g\/mL, respectively. The 95% ethanol extract of OS leaves showed a significant reduction in immobility time, restored locomotor activity, and preserved hippocampal morphology. Notably, the higher dose of OS extract (150 mg\/kg) significantly enhanced hippocampal expression of 5-HT and NE, with a moderate upregulation of BDNF. Conclusions: These findings suggest that the 95% ethanol extract of OS leaves exhibits promising antidepressant-like effects, which may be mediated through monoamine modulation and BDNF expression and partially through MAO-A enzyme inhibition.<\/jats:p>","DOI":"10.3390\/molecules31162892","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:14:01Z","timestamp":1787145241000},"page":"2892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antidepressant-like Effects of Orthosiphon stamineus: Integrated Evidence from In Silico, In Vitro, and a Reserpine-Induced Depression Model"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1457-4040","authenticated-orcid":false,"given":"Yousaf","family":"Dawood","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, Penang, Malaysia"},{"name":"College of Pharmacy, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3247-5532","authenticated-orcid":false,"given":"Atheer","family":"Zgair","sequence":"additional","affiliation":[{"name":"College of Pharmacy, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4138-711X","authenticated-orcid":false,"given":"Mun Fei","family":"Yam","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1181-3969","authenticated-orcid":false,"given":"Nur Hidayah Kaz","family":"Abdul Aziz","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jpsychires.2024.07.054","article-title":"Change in the global burden of depression from 1990\u20132019 and its prediction for 2030","volume":"178","author":"Zhang","year":"2024","journal-title":"J. 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