Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Bioactive Substance and Function of Natural Medicine, 1 Xian Nong Tan Street, Beijing, 100050, China.
Neuroscience. 2012 Jan 27;202:396-404. doi: 10.1016/j.neuroscience.2011.11.036. Epub 2011 Nov 25.
The pathogenesis of Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in substantia nigra (SNpc). FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental Parkinson's disease (PD) models. However, it is still unclear whether FLZ protects against PD through regulating the function of dopaminergic system. In this study, we carried out a set of in vitro and in vivo experiments to address these questions. Oral administration of FLZ significantly improved motor dysfunction of mice challenged by MPTP. The beneficial effects of FLZ on motor behavior attributed to the elevation of dopamine level in striatum, tyrosine hydroxylase (TH)-positive cells, and TH activity in the middle brain of mouse. Mechanism study showed that treatment of FLZ increased the phosphorylation of activating protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Using LY294002 to block phosphoinositide 3-kinases (PI3K)/Akt signaling pathway prevented the phosphorylation of mTOR and attenuated the neuroprotection of FLZ in MN9D cells challenged by MPP(+). In addition, FLZ reduced the expression of RTP801, an important protein in PD, in mice and cells intoxicated by MPTP/MPP(+). Taken together, these results revealed a novel role that FLZ elevated TH expression and activity in dopaminergic neuron through activation of Akt/mTOR survival pathway and inhibition of RTP801 in MPTP/MPP(+)-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising anti-PD drug.
帕金森病的发病机制的特征是黑质（SNpc）中的多巴胺能神经元进行性退化。FLZ，一种从中国草药中提取的新型合成角鲨烷衍生物，已被证明在实验性帕金森病（PD）模型中具有神经保护作用。然而，FLZ 是否通过调节多巴胺能系统的功能来保护 PD 仍不清楚。在这项研究中，我们进行了一系列的体外和体内实验来解决这些问题。FLZ 的口服给药显著改善了 MPTP 挑战的小鼠的运动功能障碍。FLZ 对运动行为的有益作用归因于纹状体多巴胺水平、酪氨酸羟化酶（TH）阳性细胞和小鼠中脑 TH 活性的升高。机制研究表明，FLZ 处理增加了激活蛋白激酶 B（Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化。使用 LY294002 阻断磷酸肌醇 3-激酶（PI3K）/Akt 信号通路可阻止 mTOR 的磷酸化，并减弱 FLZ 在 MPP(+) 挑战的 MN9D 细胞中的神经保护作用。此外，FLZ 减少了在 MPTP/MPP(+)中毒的小鼠和细胞中 RTP801 的表达，RTP801 是 PD 中的一种重要蛋白质。综上所述，这些结果揭示了 FLZ 通过激活 Akt/mTOR 存活途径和抑制 MPTP/MPP(+)诱导的 PD 模型中的 RTP801，提高多巴胺能神经元中 TH 表达和活性的新作用。该数据还为 FLZ 具有强大的神经保护作用提供了证据，并可能成为一种新的有前途的抗 PD 药物。
