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<p>Nicotine—an abundant tobacco alkaloid—has been epidemiologically linked to a lower incidence of Parkinson’s disease (PD). In a 6‑hydroxydopamine (6‑OHDA) rat model, we found that chronic nicotine (1.5&#xa0;mg&#xa0;kg<sup>−1</sup>&#xa0;day<sup>−1</sup>) was associated with better motor performance and a smaller drop in striatal brain‑derived neurotrophic factor (BDNF) (<i>p</i> &lt; 0.05). Untargeted lipidomics indicated partial normalization of 6‑OHDA‑induced changes in sphingolipids, phospholipids, and neutral lipids, alongside reduced lipid‑peroxidation markers. In SH‑SY5Y cells, nicotine attenuated 6‑OHDA‑related cytotoxicity, mitochondrial stress, and α‑synuclein up‑regulation (<i>p</i> &lt; 0.001); these benefits were lost when α7‑nicotinic acetylcholine receptors (α7‑nAChRs) were pharmacologically blocked. Nicotine also correlated with lower serum/striatal IL‑1β and higher IL‑10, again in an α7‑dependent manner. Because striatal cholesterol changes followed the same receptor requirement, lipid balance may be linked to the anti‑inflammatory profile. Taken together, the data support the idea that α7‑nAChR signaling contributes to nicotine’s metabolic and immunomodulatory effects in this acute toxin model, and they highlight α7‑selective agonists as candidates for safer PD intervention; definitive causality, however, will require direct lipid and cytokine manipulation studies in progressive, α‑synuclein-based models.</p>

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Nicotine Attenuates Pathogenesis of Parkinson’s Disease via α7-nAChR-Mediated Lipid Metabolic Reprogramming and Anti-inflammatory Signaling

  • 期刊论文

  • 发表日期：

    2025年6月9日

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  • Jingjing Yang,
  • Yingyan Li,
  • Hongjuan Wang,
  • Xin Li,
  • Huan Chen,
  • Hongwei Hou,
  • Qingyuan Hu

摘要

Nicotine—an abundant tobacco alkaloid—has been epidemiologically linked to a lower incidence of Parkinson’s disease (PD). In a 6‑hydroxydopamine (6‑OHDA) rat model, we found that chronic nicotine (1.5 mg kg−1 day−1) was associated with better motor performance and a smaller drop in striatal brain‑derived neurotrophic factor (BDNF) (p < 0.05). Untargeted lipidomics indicated partial normalization of 6‑OHDA‑induced changes in sphingolipids, phospholipids, and neutral lipids, alongside reduced lipid‑peroxidation markers. In SH‑SY5Y cells, nicotine attenuated 6‑OHDA‑related cytotoxicity, mitochondrial stress, and α‑synuclein up‑regulation (p < 0.001); these benefits were lost when α7‑nicotinic acetylcholine receptors (α7‑nAChRs) were pharmacologically blocked. Nicotine also correlated with lower serum/striatal IL‑1β and higher IL‑10, again in an α7‑dependent manner. Because striatal cholesterol changes followed the same receptor requirement, lipid balance may be linked to the anti‑inflammatory profile. Taken together, the data support the idea that α7‑nAChR signaling contributes to nicotine’s metabolic and immunomodulatory effects in this acute toxin model, and they highlight α7‑selective agonists as candidates for safer PD intervention; definitive causality, however, will require direct lipid and cytokine manipulation studies in progressive, α‑synuclein-based models.