Ruan Sisi, Xie Jiqing, Wang Linhai, Guo Lulu, Li Yan, Fan Wu, Ji Rongzhan, Gong Zhenlin, Xu Yan, Mao Jian, Xie Jianping
Flavour Science Research Center, College of Chemistry, Zhengzhou University, Zhengzhou, China.
Zhengzhou Tobacco Research Institute of CNTC, Zhengzhou, China.
Front Pharmacol. 2023 Feb 2;14:1088957. doi: 10.3389/fphar.2023.1088957. eCollection 2023.
Nicotine (Nic) has previously been proven to reduce neurodegeneration in the models of Parkinson's disease (PD). The present study is intended to investigate the detailed mechanisms related to the potential neuroprotective effects of Nic . We established a PD model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL6 mice (25 mg/kg/d, 5 d, i.p.) to investigate the neuropharmacological modulation of Nic pretreatment (2.5 mg/kg/d, 5 d, i.p., 30 min before MPTP injection) from the perspectives of neurobehavioral assessment, the pathological alterations, microglial cell inflammation and MAPK signaling pathways in specific brain regions. The open field test, elevated plus maze, rotarod and traction test suggested that Nic pretreatment could significantly improve MPTP-induced motor impairment and had an anxiolytic effect. Nic was found to improve neuroapoptosis, enhance tyrosine hydroxylase activity, and reduce the accumulation of the phosphorylated α-synuclein in the substantia nigra and striatal regions of PD mice by TUNEL and immunohistochemical assays. Immuno-fluorescent method for labeling Iba1 and CD68 indicated that Nic remarkably alleviates the activation of microglia which represents the M1 polarization state in the mice brain under MPTP stimulation. No significant difference in the expression of p38/MAPK pathway was found in the nigrostriatal regions, while Nic could significantly inhibit the elevated p-JNK/JNK ratio and increase the declined p-ERK/ERK ratio in the substantia nigra of MPTP-exposed brains, which was further confirmed by the pretreatment of CYP2A5 inhibitor to decline the metabolic activity of Nic. The molecular signaling mechanism by which Nic exerts its neuroprotective effects against PD may be achieved by regulating the JNK and ERK signaling pathways in the nigra-striatum related brain regions.
尼古丁（Nic）先前已被证明可减轻帕金森病（PD）模型中的神经退行性变。本研究旨在探讨与Nic潜在神经保护作用相关的详细机制。我们使用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的C57BL6小鼠（25mg/kg/d，5天，腹腔注射）建立了PD模型，从神经行为评估、病理改变、小胶质细胞炎症和特定脑区的MAPK信号通路等角度研究Nic预处理（2.5mg/kg/d，5天，腹腔注射，在MPTP注射前30分钟）的神经药理学调节作用。旷场试验、高架十字迷宫试验、转棒试验和牵引试验表明，Nic预处理可显著改善MPTP诱导的运动障碍，并具有抗焦虑作用。通过TUNEL和免疫组织化学分析发现，Nic可改善神经细胞凋亡，增强酪氨酸羟化酶活性，并减少PD小鼠黑质和纹状体区域磷酸化α-突触核蛋白的积累。免疫荧光法标记Iba1和CD68表明，Nic可显著减轻MPTP刺激下小鼠脑中代表M1极化状态的小胶质细胞的激活。在黑质纹状体区域，p38/MAPK通路的表达没有显著差异，而Nic可显著抑制MPTP暴露脑黑质中升高的p-JNK/JNK比值，并增加下降的p-ERK/ERK比值，CYP2A5抑制剂预处理降低Nic的代谢活性进一步证实了这一点。Nic对PD发挥神经保护作用的分子信号机制可能是通过调节黑质纹状体相关脑区的JNK和ERK信号通路来实现的。
