ArticleBiology of sex differences2026
Sex-specific metabolic and microbial remodeling in a rotenone-induced rat model of Parkinson's disease following nicotine administration.
Article in Biology of sex differences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundParkinson's disease (PD) is a neurodegenerative disorder with established sex differences in incidence and progression. Epidemiological evidence suggests nicotine may confer protection against PD, but its mechanisms, particularly regarding sex-specific effects, remain unclear. This study investigated the neuroprotective mechanisms of nicotine in a rotenone-induced PD rat model, with a specific focus on evaluating sex-dependent modulation across behavioral, pathological, and gut-related outcomes.
methodsMale and female Sprague-Dawley rats were administered rotenone (2 mg/kg/day, s.c.) for four weeks to induce PD. Nicotine (0.5 mg/kg/day, s.c.) was administered 30 min after rotenone. Motor function was assessed using rotarod and CatWalk XT gait analysis. Neuropathology in the substantia nigra was evaluated via immunofluorescence for α-synuclein and tyrosine hydroxylase (TH). Gut pathology was analyzed through colon histopathology (H&E staining) and ELISA for IL-6 and α-synuclein. Gut microbiota composition was assessed by 16 S rDNA sequencing, and serum metabolomics was performed using UPLC-MS/MS. Data were analyzed by two-way ANOVA with Tukey's post-hoc test.
resultsNicotine significantly attenuated rotenone-induced motor impairments: males showed a superior response in balance-related parameters, while females exhibited enhanced efficacy in dynamic gait metrics. Pathologically, nicotine reduced nigral α-synuclein accumulation and TH depletion in both sexes, with males showing greater α-synuclein accumulation following rotenone exposure. Crucially, nicotine exclusively ameliorated colon histopathology, reduced plasma α-synuclein, and suppressed colon IL-6 in females, while attenuating intestinal α-synuclein accumulation in both sexes. Microbiota analysis revealed sex-divergent taxonomic shifts with nicotine treatment. Metabolomics showed significantly more extensive metabolic reprogramming in females, particularly affecting indole derivatives. Pearson correlations revealed significant sex-specific associations between altered serum indole derivatives and gut microbiota genera.
conclusionsNicotine exerts neuroprotection in PD through sex-dependent modulation of multiple pathological pathways, primarily involving the gut-microbiota-metabolite axis. Females benefit from enhanced gastrointestinal protection and metabolic reprogramming, while males show preferential motor balance restoration. These findings underscore the critical importance of sex-stratified therapeutic strategies for PD.
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