Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models
Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models
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DOI：
10.1016/j.brainres.2013.12.026
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发表时间：
2014-02-14
期刊：
影响因子：
2.9
通讯作者：
Zhang, Dan
中科院分区：
文献类型：
--
作者：
Bao, Xiu-Qi;Kong, Xiang-Chen;Zhang, Dan
帕金森病（PD）是一种影响黑质纹状体通路中高达80%的多巴胺能神经元的神经退行性疾病。FLZ是一种新的从中草药中合成的squamosamide衍生物，已被证明在实验性PD模型中具有神经保护作用。本研究通过一系列体内外实验，探讨FLZ的神经保护作用及其机制。结果表明，FLZ能明显改善6-羟基多巴胺（6-OHDA）损伤大鼠的运动功能障碍和多巴胺能神经元丢失。FLZ的有益作用归因于多巴胺能神经元数目、多巴胺水平和酪氨酸羟化酶（TH）活性的增加。FLZ可能通过抑制α-突触核蛋白（alpha-Syn）的表达及与TH的相互作用而保护TH活性和多巴胺能神经元。进一步的研究表明磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路参与FLZ的神经保护作用，阻断PI 3 K/Akt信号通路可抑制α-Syn的表达，减弱FLZ的神经保护作用。此外，FLZ治疗降低了参与PD发病机制的重要蛋白RTP 801的表达。综上所述，这些结果表明FLZ通过激活Akt存活通路抑制6-OHDA诱导的PD模型中多巴胺能神经元的α-Syn表达和升高TH活性。FLZ具有较强的神经保护作用，有望成为PD治疗的新药物。(C)2013爱思唯尔有限公司版权所有。
Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats ihjured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and doparninergic neurons through decreasing alpha-synuclein (alpha-Syn) expression and the interaction between alpha-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of a-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed alpha-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment. (C) 2013 Elsevier B.V. All rights reserved.