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Conventional therapies relieve early PD symptoms, but they do not repair dopaminergic neurons. Berberine (BBR) and caffeine (CAF), both natural alkaloids, exhibited neuroprotective effects in many neurodegenerative disorders. Consequently, we hypothesized that the combination of BBR and CAF therapies would offer protection against PD-related impairments in the rotenone (ROT)-induced rat model when compared to the commercial drug, metformin (MTF). Our results showed that the combined administration of BBR (25 mg\/kg\/day) and CAF (2.5 mg\/kg\/day) for four weeks prevented motor deficits, weight reduction, dopamine (DA) depletion, and monoamine oxidase (MAO) activity in ROT-induced rats in comparison with monotherapy of BBR and CAF along with MTF. This combination produced a notable neuroprotective effect by reducing tumor necrosis factor (TNF)-\u03b1 and interleukin-16 (IL-6) in midbrain of rats. BBR and CAF combinations markedly normalized tyrosine hydroxylase (TH) levels and decreased total \u03b1-syn and \u03b1-syn-p<jats:sup>ser129<\/jats:sup> aggregation and increased protein phosphatase 2A (PP2A) levels. Histological analysis indicated that damaged neurons exhibited significant amelioration with the co-administration of BBR and CAF. The molecular docking results indicated that both BBR and CAF had notable binding affinity for the protein pocket surrounding the \u03b1-syn, PP2A, and TH in comparison to MTF. They are predicted to serve as effective inhibitors of enzyme-mediated phosphorylation of \u03b1-syn-<jats:sup>pser129<\/jats:sup>. Conclusively, combined BBR and CAF administration presents a novel strategy for neuroprotection by blocking the initial events in PD incidence, demonstrating considerable anti-oxidative and anti-inflammatory benefits relative to MTF.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1007\/s10787-025-01661-w","type":"journal-article","created":{"date-parts":[[2025,3,9]],"date-time":"2025-03-09T11:27:11Z","timestamp":1741519631000},"page":"2129-2150","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Neuroprotective efficacy of berberine and caffeine against rotenone\u2010induced neuroinflammatory and oxidative disturbances associated with Parkinson\u2019s disease via inhibiting \u03b1-synuclein aggregation and boosting dopamine release"],"prefix":"10.1007","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5988-6883","authenticated-orcid":false,"given":"Tasnim S.","family":"Waheeb","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A.","family":"Abdulkader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa A.","family":"Ghareeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed E.","family":"Moustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,9]]},"reference":[{"key":"1661_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2023.102315","volume":"132","author":"TA Adeyeye","year":"2023","unstructured":"Adeyeye TA, Babatunde BR, Ehireme SE, Shallie PD (2023) Caffeine alleviates anxiety-like behavior and brainstem lesions in a rotenone-induced rat model of Parkinson\u2019s disease. 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