Bao Xiu-Qi, Wu Liang-Yu, Wang Xiao-Liang, Sun Hua, Zhang Dan
State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,
Naunyn Schmiedebergs Arch Pharmacol. 2015 May;388(5):549-56. doi: 10.1007/s00210-015-1094-5. Epub 2015 Feb 13.
Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder characterized by motor impairments and loss of dopaminergic neurons in the substantia nigra. FLZ (formulated as: N-2-(4-hydroxy-phenyl)-ethyl]-2-(2, 5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic derivative of squamosamide from a Chinese herb and has been proven to protect dopaminergic neurons in subacute PD models. However, whether FLZ has a neuroprotective effect on chronic PD model is still unknown. The present study was designed to verify the neuroprotection of FLZ on chronic PD mouse model induced by MPTP combined with probenecid (MPTP/p). The results showed that treatment of mice with FLZ for 9 weeks significantly improved motor behavior and dopaminergic neuronal function of mice injected with MPTP/p. The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level, and tyrosine hydroxylase (TH) activity, as well as decrease of α-synuclein (α-Syn) expression, α-Syn phosphorylation, nitration, and aggregation. Moreover, FLZ decreased the interaction between α-Syn and TH, which eventually improved dopaminergic neuronal function. Mechanistic study demonstrated that FLZ increased Akt and mTOR phosphorylation, suggesting that FLZ activated Akt/mTOR signaling pathway and this might be involved in the neuroprotection of FLZ. The present results provided more elaborate in vivo evidences to support the neuroprotective effect of FLZ on dopaminergic neurons of chronic PD mouse model and the potential of FLZ to be developed as new drug to treat PD.
帕金森病（PD）是一种慢性进行性神经退行性疾病，其特征为运动功能障碍以及黑质中多巴胺能神经元的丧失。FLZ（化学结构式为：N-2-(4-羟基-苯基)-乙基]-2-(2,5-二甲氧基-苯基)-3-(3-甲氧基-4-羟基-苯基)-丙烯酰胺）是一种源自中药蛇床子素的新型合成衍生物，已被证实在亚急性PD模型中可保护多巴胺能神经元。然而，FLZ对慢性PD模型是否具有神经保护作用仍不清楚。本研究旨在验证FLZ对由MPTP联合丙磺舒（MPTP/p）诱导的慢性PD小鼠模型的神经保护作用。结果显示，用FLZ治疗小鼠9周可显著改善注射MPTP/p小鼠的运动行为和多巴胺能神经元功能。FLZ的有益作用归因于多巴胺能神经元数量、多巴胺水平和酪氨酸羟化酶（TH）活性的升高，以及α-突触核蛋白（α-Syn）表达、α-Syn磷酸化、硝化和聚集的减少。此外，FLZ减少了α-Syn与TH之间的相互作用，最终改善了多巴胺能神经元功能。机制研究表明，FLZ增加了Akt和mTOR的磷酸化，提示FLZ激活了Akt/mTOR信号通路，这可能参与了FLZ的神经保护作用。本研究结果提供了更详尽的体内证据，以支持FLZ对慢性PD小鼠模型多巴胺能神经元的神经保护作用，以及FLZ作为治疗PD新药的开发潜力。
