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This study investigates the neuroprotective potential of <jats:italic>Pelargonium graveolens<\/jats:italic> (Thunb.) L\u2019H\u00e9r leaves in a rotenone-induced PD rat model. The total ethanolic extract and its fractions, obtained via Diaion HP-20 column chromatography, were evaluated for monoamine oxidase-B (MAO-B) inhibition <jats:italic>in vitro<\/jats:italic>. The 50% methanol fraction (PG50) demonstrated the highest MAO-B inhibition (IC<jats:sub>50<\/jats:sub> 5.26\u2009\u00b1\u20090.12\u00a0\u00b5g\/ml) compared to the reference drug selegiline (IC<jats:sub>50<\/jats:sub> 0.021\u2009\u00b1\u20090.003\u00a0\u00b5g\/ml). In a rotenone-induced PD rat model, PG50 (100\u00a0mg\/kg, <jats:italic>p.o<\/jats:italic>.) alleviated motor deficits (assessed via the wire hanging test), and restored norepinephrine, dopamine, and serotonin levels. PG50 and <jats:sc>l<\/jats:sc>-dopa reduced \u03b1-synuclein levels by 367.60% and 377.48%, respectively. Oxidative balance was restored with increased glutathione (23.12%) and decreased malondialdehyde (164.19%) in brain tissues. PG50 significantly reduced serum TNF-\u03b1 (572.79%) and IL-6 (70.84%)\u00a0levels, and improved succinate dehydrogenase (14.47%) and lactate dehydrogenase (7.74%) activities in brain tissues. Histopathological alterations in the SN were also ceased. UPLC-MS\/MS analysis identified 61 metabolites, including 32 flavonoids, 13 phenolic acids, 7 coumarins, 5 phenolic glycosides, and 4 dicarboxylic acids, with in silico docking showing strong MAO-B binding by methoxylated flavonoids like methoxyluteolin dimethyl ether (docking score:\u2009\u2212\u20098.0625\u00a0kcal\/mol), surpassing that of safinamide (\u2212\u20098.2615\u00a0kcal\/mol). These findings suggest that <jats:italic>P. graveolens<\/jats:italic> holds promise as a neuroprotective agent against rotenone-induced PD.<\/jats:p>","DOI":"10.1007\/s12035-025-04727-6","type":"journal-article","created":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T13:02:06Z","timestamp":1739019726000},"page":"7664-7681","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pelargonium graveolens Attenuates Rotenone-Induced Parkinson\u2019s Disease in a Rat Model: Role of MAO-B Inhibition and In Silico Study"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3363-5681","authenticated-orcid":false,"given":"Rana M.","family":"Merghany","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma A.","family":"El-Sawi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa F. 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