Li Jiang, Xu Shaofeng, Wang Ling, Wang Xiaoliang
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Pharmaceuticals (Basel). 2023 Feb 15;16(2):305. doi: 10.3390/ph16020305.
Diabetes mellitus (DM) has been recognized as an increased risk factor for cognitive impairment, known as diabetic encephalopathy (DE). Hyperglycemia and insulin resistance are the main initiators of DE, which is related to the accumulation of advanced glycation end products (AGEs). Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a derivative of 3-n-butylphthalide (dl-NBP), has emerged various properties including improved mitochondrial function, antioxidant, anti-neuroinflammation, and neuroprotective effects. The present study aimed to investigate the neuroprotective effect of PHPB against AGEs accumulation in type 2 diabetic KK-Ay mice model with DE and further explore the underlying mechanisms. The results showed that PHPB markedly ameliorated the spatial learning ability of KK-Ay mice in the Morris water maze and decreased AD-like pathologic changes (Tau hyperphosphorylation) in the cortex. Furthermore, we found that PHPB treatment significantly reduced AGEs generation via up-regulation of glyoxalase-1 (GLO1) protein and enhancement of methylglyoxal (MG) trapping, while there was no obvious difference in levels of glucose in plasma or brain, contents of total cholesterol (TC), triglycerides (TG), and plasma insulin. Also, PHPB treatment improved the insulin signaling pathway by increasing sirtuin1 (SIRT1) deacetylase activity and attenuated oxidative stress evidenced by elevating glucose-6-phosphate dehydrogenase (G-6-PD) protein expression, promoting the production of reduced glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), restoring mitochondrial membrane potential, increasing adenosine triphosphate (ATP) generation, and reducing malondialdehyde (MDA) levels in the brain. Taken together, PHPB exhibited a beneficial effect on DE, which involved modulating the SIRT1/insulin signaling pathway and reducing oxidative stress by inhibiting the generation of AGEs.
糖尿病（DM）已被公认为是认知障碍的一个风险增加因素，即糖尿病性脑病（DE）。高血糖和胰岛素抵抗是DE的主要引发因素，这与晚期糖基化终产物（AGEs）的积累有关。2-（1-羟戊基）-苯甲酸钾（PHPB）是3-正丁基苯酞（dl-NBP）的衍生物，具有多种特性，包括改善线粒体功能、抗氧化、抗神经炎症和神经保护作用。本研究旨在探讨PHPB对2型糖尿病伴DE的KK-Ay小鼠模型中AGEs积累的神经保护作用，并进一步探索其潜在机制。结果表明，PHPB显著改善了KK-Ay小鼠在莫里斯水迷宫中的空间学习能力，并减少了皮质中类似阿尔茨海默病的病理变化（Tau过度磷酸化）。此外，我们发现PHPB治疗通过上调乙二醛酶-1（GLO1）蛋白和增强甲基乙二醛（MG）捕获显著减少了AGEs的生成，而血浆或脑中的葡萄糖水平、总胆固醇（TC）、甘油三酯（TG）含量和血浆胰岛素水平没有明显差异。此外，PHPB治疗通过增加沉默调节蛋白1（SIRT1）脱乙酰酶活性改善了胰岛素信号通路，并减轻了氧化应激，这表现为葡萄糖-6-磷酸脱氢酶（G-6-PD）蛋白表达升高、促进还原型谷胱甘肽（GSH）和还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的产生、恢复线粒体膜电位、增加三磷酸腺苷（ATP）生成以及降低脑中丙二醛（MDA）水平。综上所述，PHPB对DE具有有益作用，其涉及调节SIRT1/胰岛素信号通路并通过抑制AGEs生成来减轻氧化应激。
