Effects and mechanisms of nicotine on dopamine release in Parkinson’s disease mouse model
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摘要:
目的：研究烟碱对帕金森病（Parkinson’s disease，PD）模型小鼠不同脑区多巴胺（dopamine，DA）的影响及其机制。方法:应用1-甲基-4-苯基-1，2，3，6-四氢吡啶（1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine，MPTP）制备PD小鼠模型，应用爬杆实验检测小鼠运动功能，应用酪氨酸羟化酶免疫组化观察小鼠中脑黑质致密部（substantia nigra pars compacta， SNpc）多巴胺能神经元数目，应用高效液相色谱法检测小鼠不同脑区（纹状体、海马、皮质）DA的含量，应用蛋白质免疫印迹检测小鼠纹状体多巴胺转运体（dopamine transporter，DAT）的变化。结果：①烟碱可显著改善MPTP导致的野生型小鼠运动功能障碍；②烟碱可显著改善MPTP诱导的野生型小鼠中脑SNpc多巴胺能神经元的丢失；③烟碱可显著减轻MPTP所致的野生型小鼠纹状体DA含量的减少，烟碱对α7-烟碱型乙酰胆碱受体（nicotinic acetylcholine receptors，nAChRs）敲除型（knockout，KO）小鼠MPTP模型中纹状体DA含量的减少无明显恢复作用，烟碱对野生型小鼠或α7-nAChRs KO小鼠MPTP模型中海马和皮质中的DA含量无明显影响。④烟碱可显著增加野生型小鼠MPTP模型中纹状体DAT的含量，烟碱对α7-nAChRs KO小鼠MPTP模型中的纹状体DAT的减少无逆转作用。结论：烟碱可以激活α7-nAChRs抑制PD模型小鼠SNpc区多巴胺能神经元的死亡，提高纹状体DAT水平；促进纹状体DA含量增加，从而在PD模型小鼠中发挥神经保护作用。
Abstract:
Objective: To study on effects and mechanisms of nicotine on dopamine (DA) release in different brain regions of mice model with Parkinson’s disease(PD). Methods: PD mice were established by 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine (MPTP). Motor function was detected by pole climbing test. The number of dopaminergic neuron in mice midbrain substantia nigra pars compacta(SNpc) region was detected using tyrosine hydroxylase immunohistochemistry. High performance liquid chromatography was used to determine the content of DA in different brain regions (the striatum， hippocampus and cortex). Striatal dopamine transporter (DAT) levels were detected by Western blot. Results: ①Nicotine significantly improved MPTP-induced motor function deficits in wild-type mice; ②Nicotine significantly prevented MPTP-induced dopaminergic neuron loss in wild-type mice SNpc; ③Nicotine significantly inhibited MPTP-induced decrease of striatal DA content in wildtype mice. Nicotine had no significant effect on MPTP-induced decrease of striatal DA content in α7-nicotinic acetylcholine receptors(α7-nAChRs) knockout mice. Nicotine had no obvious effect on DA content in the hippocampus and cortex of MPTP model in wild-type mice or knockout mice. ④Nicotine significantly increased the content of DAT in the striatum of MPTP model in wild-type mice. Nicotine had no effect on MPTP-induced decrease of DAT in the striatum of MPTP model in α7-nAChRs knockout mice. Conclusion: Nicotine inhibits the death of dopaminergic neurons in SNpc region of PD mice and improves striatal DAT levels through the activation of α7-nAChRs. Nicotine promotes the increase of striatal DA content， and exerts neuroprotective effects in PD mice.
