Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.

中文翻译：

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Platycodin D 通过调节 PI3K/Akt/GSK3β 信号通路改善 2 型糖尿病小鼠的认知障碍

目的：本研究的目的是探讨桔梗皂苷 D (PD) 对 2 型糖尿病 (T2DM) 认知功能障碍的改善作用及其体内和体外潜在的分子作用机制。材料和方法： C57BL/6小鼠高脂饮食8周后腹腔注射链脲佐菌素（100 mg/kg），建立T2DM认知障碍动物模型。在体外，采用免疫荧光染色和蛋白质印迹分析PD对葡萄糖诱导的小鼠海马神经元细胞（HT22）神经毒性的影响。结果： PD（2.5 mg/kg）治疗4周显着抑制T2DM小鼠空腹血糖升高，改善胰岛素分泌不足，逆转血清甘油三酯、胆固醇、低密度脂蛋白和高密度脂蛋白水平异常。同时，PD可改善T2DM小鼠的胆碱功能障碍，并抑制氧化应激和caspase家族凋亡相关蛋白的产生。值得注意的是，PD 剂量依赖性地防止线粒体膜电位损失，在体外促进磷脂酰肌醇 3 激酶和蛋白激酶 B (Akt) 的磷酸化，激活 Ser9 位点的糖原合酶激酶 3β (GSK3β) 表达，并抑制 Tau 蛋白过度磷酸化。结论：这些结果清楚地表明PD可以减轻T2DM引起的神经损伤，而Akt Ser473位点的磷酸化可能是其作用的关键。