Wu Dong-Mei, Han Xin-Rui, Wen Xin, Wang Shan, Fan Shao-Hua, Zhuang Juan, Wang Yong-Jian, Zhang Zi-Feng, Li Meng-Qiu, Hu Bin, Shan Qun, Sun Chun-Hui, Lu Jun, Zheng Yuan-Lin
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.
College of Health Sciences, Jiangsu Normal University, Xuzhou, China.
Cell Physiol Biochem. 2018;46(5):1793-1806. doi: 10.1159/000489365. Epub 2018 Apr 25.
BACKGROUND/AIMS: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and recent studies suggested that oxidative stress (OS) contributes to the cascade that leads to dopamine cell degeneration in PD. In this study, we hypothesized that salidroside (SDS) offers protection against OS injury in 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats as well as the underlying mechanism.
SDS and LiCl (activators of the Wnt/β-catenin signaling pathway) administration alone and in combination with 6-OHDA injection in rats was performed 3 days before modeling for 17 consecutive days to verify the regulatory mechanism by which SDS affects the Wnt/β-catenin signaling pathway as well as to evaluate the protective effect of SDS on PD in relation to OS in vivo. In addition, pheochromocytoma 12 (PC12) cells were incubated with 10 µmol/L SDS or LiCl alone or with both in combination for 1 h followed by a 24-h incubation with 100 µmol/L 6-OHDA to obtain in vitro data.
In vivo the administration of LiCl was found to ameliorate behavioral deficits and dopaminergic neuron loss; increase superoxide dismutase (SOA) activity, glutathione peroxidase (GSH-Px) levels, and glycogen synthase kinase 3β phosphorylation (GSK-3β-Ser9); reduce malondialdehyde (MDA) accumulation in the striatum and the GSK-3β mRNA level; as well as elevate β-catenin and cyclinD1 mRNA and protein levels in 6-OHDA-injected rats. This SDS treatment regimen was found to strengthen the beneficial effect of LiCl on 6-OHDA-injected rats. In vitro LiCl treatment decreased the toxicity of 6-OHDA on PC12 cells and prevented apoptosis. Additionally, LiCl treatment increased SOA activity, GSH-Px levels, and GSK-3β-Ser9 phosphorylation; decreased MDA accumulation in the striatum and GSK-3β mRNA levels; as well as increased β-catenin and cyclinD1 mRNA and protein levels in 6-OHDA-treated PC12 cells. Additionally, SDS treatment increased the protective effect of LiCl on 6-OHDA-treated PC12 cells.
Evidence from experimental models suggested that SDS may confer neuroprotection against the neurotoxicity of 6-OHDA in response to OS injury and showed that these beneficial effects may be related to regulation of the Wnt/β-catenin signaling pathway. Therefore, SDS might be a potential therapeutic agent for treating PD.
背景/目的：帕金森病（PD）是仅次于阿尔茨海默病的第二常见神经退行性疾病，最近的研究表明氧化应激（OS）促成了导致PD中多巴胺能细胞变性的级联反应。在本研究中，我们假设红景天苷（SDS）可保护单侧6-羟基多巴胺（6-OHDA）损伤的大鼠免受OS损伤及其潜在机制。
在建模前3天，连续17天单独或联合给予大鼠SDS和LiCl（Wnt/β-连环蛋白信号通路激活剂）并注射6-OHDA，以验证SDS影响Wnt/β-连环蛋白信号通路的调节机制，并评估SDS在体内对与OS相关的PD的保护作用。此外，将嗜铬细胞瘤12（PC12）细胞分别单独或联合用10 μmol/L SDS或LiCl孵育1小时，然后用100 μmol/L 6-OHDA孵育24小时以获得体外数据。
在体内，发现给予LiCl可改善行为缺陷和多巴胺能神经元损失；增加超氧化物歧化酶（SOA）活性、谷胱甘肽过氧化物酶（GSH-Px）水平和糖原合酶激酶3β磷酸化（GSK-3β-Ser9）；减少纹状体中丙二醛（MDA）积累和GSK-3β mRNA水平；以及提高6-OHDA注射大鼠中β-连环蛋白和细胞周期蛋白D1 mRNA和蛋白水平。发现这种SDS治疗方案可增强LiCl对6-OHDA注射大鼠的有益作用。在体外，LiCl处理降低了6-OHDA对PC12细胞的毒性并防止细胞凋亡。此外，LiCl处理增加了SOA活性、GSH-Px水平和GSK-3β-Ser9磷酸化；降低了纹状体中MDA积累和GSK-3β mRNA水平；以及提高了6-OHDA处理的PC12细胞中β-连环蛋白和细胞周期蛋白D1 mRNA和蛋白水平。此外，SDS处理增强了LiCl对6-OHDA处理的PC12细胞的保护作用。
实验模型的证据表明SDS可能对6-OHDA的神经毒性具有神经保护作用，以应对OS损伤，并表明这些有益作用可能与Wnt/β-连环蛋白信号通路的调节有关。因此，SDS可能是治疗PD的潜在治疗剂。
