Vortioxetine attenuates rotenone-induced enteric neuroinflammation via modulation of the TLR2/S100B/RAGE signaling pathway in a rat model of Parkinson's disease

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dc.authorid0000-0002-3359-3899
dc.authorid0009-0008-3117-0092
dc.authorid0000-0002-3616-0052
dc.authorid0000-0001-5284-7439
dc.contributor.authorSamur, Dilara Nemutlu
dc.contributor.authorYildirim, Sendegul
dc.contributor.authorMaytalman, Erkan
dc.contributor.authorKalay, Merzuka
dc.contributor.authorTanriover, Gamze
dc.contributor.authorOzbey, Gul
dc.date.accessioned2026-01-24T12:31:16Z
dc.date.available2026-01-24T12:31:16Z
dc.date.issued2025
dc.departmentAlanya Alaaddin Keykubat Üniversitesi
dc.description.abstractEmerging evidence suggests that gastrointestinal dysfunction and enteric nervous system pathology play a critical role in the early stages of Parkinson's disease. Considering the bidirectional relationship between gastrointestinal symptoms and mood disorders, this study aimed to elucidate the effects and possible mechanisms of action of vortioxetine, a serotonergic antidepressant, on the pathophysiological changes induced by rotenone in the enteroglial cells. alpha-synuclein, phosphorylated alpha-synuclein, TLR2, S100B and RAGE expression were detected in duodenal tissues of rats administered rotenone (2 mg/kg/day, s.c.) and/or vortioxetine (10 mg/kg/ day, s.c.) for 28 days. For the mechanism of action studies, rat-derived enteroglial cells were treated with rotenone (10 mu M) and/or vortioxetine (5 mu M or 1 mu M) for 24 h. The effects of vortioxetine were evaluated in the presence of the TLR2 antagonist C29, RAGE antagonist FPS-ZM1 and the S100B inhibitor pentamidine. TLR2, S100B, RAGE, and NF kappa B mRNA levels and proinflammatory cytokines via RT-qPCR and ELISA. Our results demonstrate that rotenone treatment significantly increased alpha-synuclein, pS129-alpha-synuclein, TLR2, and S100B expression while reducing RAGE levels, indicating marked enteric pathology. Vortioxetine administration attenuated these effects, reducing alpha-synuclein accumulation and proinflammatory markers. In vitro, rotenone impaired glial responses, decreasing S100B, RAGE, and NF kappa B markers, while vortioxetine improved these responses, promoting resynthesis of inflammatory molecules. Notably, S100B, NF kappa B, and cytokine levels (TNF-alpha, IL-1 beta, IL-6) were affected by C29, FPS-ZM1, and pentamidine pretreatments. Thus, vortioxetine is thought to have beneficial effects on rotenone-induced pathological changes in EGCs, and some of these effects are thought to be mediated by the TLR2/S100B/RAGE pathway.
dc.description.sponsorshipScientific and Technological Research Council of Turkiye (TUBITAK) [121R103]; Alanya Alaaddin Keykubat University Research Foundation [2022-04-02-MAP01]
dc.description.sponsorshipThis work was supported by grants from the Scientific and Technological Research Council of Turkiye (TUBITAK) (121R103) and Alanya Alaaddin Keykubat University Research Foundation (2022-04-02-MAP01) . We extend our gratitude to Lundbeck A/S for kindly providing vortioxetine. Special thanks to Dr. Luca Antonioli for generously providing the enteroglial cell line used in this study.
dc.identifier.doi10.1016/j.neuropharm.2025.110385
dc.identifier.issn0028-3908
dc.identifier.issn1873-7064
dc.identifier.pmid40010563
dc.identifier.scopus2-s2.0-85218860149
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://doi.org/10.1016/j.neuropharm.2025.110385
dc.identifier.urihttps://hdl.handle.net/20.500.12868/5767
dc.identifier.volume271
dc.identifier.wosWOS:001436293400001
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherPergamon-Elsevier Science Ltd
dc.relation.ispartofNeuropharmacology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WoS_20260121
dc.subjectalpha-synuclein
dc.subjectEnteric nervous system
dc.subjectEnteric glia
dc.subjectNeuroinflammation
dc.subjectParkinson's disease
dc.subjectRAGE
dc.subjectS100B
dc.subjectTLR2
dc.subjectVortioxetine
dc.titleVortioxetine attenuates rotenone-induced enteric neuroinflammation via modulation of the TLR2/S100B/RAGE signaling pathway in a rat model of Parkinson's disease
dc.typeArticle

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