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Background <p>Parkinson’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.</p> Methods <p>Male and female Sprague-Dawley rats were administered rotenone (2&#xa0;mg/kg/day, s.c.) for four weeks to induce PD. Nicotine (0.5&#xa0;mg/kg/day, s.c.) was administered 30&#xa0;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&amp;E staining) and ELISA for IL-6 and α-synuclein. Gut microbiota composition was assessed by 16&#xa0;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.</p> Results <p>Nicotine 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.</p> Conclusions <p>Nicotine 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.</p>

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Sex-specific metabolic and microbial remodeling in a rotenone-induced rat model of Parkinson’s disease following nicotine administration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月3日

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  • Zhen Ni,
  • Gaoge Wang,
  • Qian Li,
  • Xiaqing Wu,
  • Zheng Song,
  • Hao Yu,
  • Pengpeng Yu,
  • Yibo Chen,
  • Lixiang Li,
  • Huan Chen,
  • Hongwei Hou,
  • Qingyuan Hu

摘要

Background

Parkinson’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.

Methods

Male 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.

Results

Nicotine 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.

Conclusions

Nicotine 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.