黄连解毒汤调节HIF-1α/VEGF信号通路改善APP/PS1双转基因小鼠学习记忆能力的作用机制  

Huanglian Jiedutang Regulates HIF-1α/VEGF Signaling Pathway to Improve Learning and Memory Abilities of APP/PS1 Transgenic Mice

作　　者：张英华 吕翰林 周建文 樊丽 李洋 ZHANG Yinghua;LYU Hanlin;ZHOU Jianwen;FAN Li;LI Yang(College of Mental Health,Qiqihar Medical University,Qiqihar 161006,China;The First Affiliated Hospital of Qiqihar Medical University,Qiqihar 161041,China;Institute of Medical Sciences,Qiqihar Medical University,Qiqihar 161006,China)

机构地区：[1]齐齐哈尔医学院精神卫生学院,黑龙江齐齐哈尔161006 [2]齐齐哈尔医学院附属第一医院,黑龙江齐齐哈尔161041 [3]齐齐哈尔医学院医药科学研究院,黑龙江齐齐哈尔161006

出　　处：《中国实验方剂学杂志》2024年第7期59-65,共7页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：黑龙江省省属高等学校基本科研业务费科研项目(2021-KYYWF-0363);国家自然科学基金项目(81973597)。

摘　　要：目的:基于缺氧诱导因子-1α(HIF-1α)/血管内皮生长因子(VEGF)信号通路探讨黄连解毒汤(HLJDT)对淀粉样前体蛋白(APP)/早老素1(PS1)双转基因小鼠学习记忆的影响。方法:40只5月龄APP/PS1小鼠,分为模型组、多奈哌齐组(0.001 g·kg^(-1)·d^(-1))、黄连解毒汤低、中、高剂量(1.5、3、6 g·kg^(-1)·d^(-1)),C57BL/6小鼠8只为正常组。连续给药45 d,进行Morris水迷宫实验,测定脏器指数,透射电镜观察小鼠脑血管内皮细胞形态结构,蛋白免疫印迹法(Western blot)检测海马区APP、HIF-1α、VEGF、VEGFA及脑源性神经营养因子(BDNF)蛋白表达,实时荧光定量聚合酶链式反应(Real-time PCR)检测APP、HIF-1α、VEGF mRNA的表达。结果:与正常组比较,模型组小鼠潜伏期明显延长(P<0.05),目标平台周围路程及时间明显缩短(P<0.05),脑和脾脏的脏器指数明显降低(P<0.05),血管内皮细胞核固缩,胞质不丰富,海马区APP、HIF-1α、VEGF、VEGFA蛋白表达增加(P<0.05),BDNF蛋白表达降低(P<0.05),APP、HIF-1α、VEGF mRNA表达增加(P<0.05)。与模型组比较,HLJDT高剂量组潜伏期明显缩短(P<0.05),目标平台周围路程及时间延长(P<0.05),脑和脾脏的脏器指数明显升高(P<0.05),血管内皮细胞细胞器结构较清晰,海马区APP、HIF-1α、VEGF、VEGFA蛋白表达降低(P<0.05),BDNF蛋白表达增加(P<0.05),APP、HIF-1α、VEGF mRNA表达降低(P<0.05)。结论:HLJDT可通过降低HIF-1α和VEGF表达来提高小鼠学习记忆能力,从而发挥对神经的保护作用。Objective:To reveal the effects of Huanglian Jiedutang (HLJDT) on the learning and memory abilities of APP/PS1 transgenic mice via hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway.Method:Forty 5-month-old β-amyloid precursor protein (APP)/presenilin 1(PS1) mice were randomized into the model,donepezil (0.001 g·kg^(-1)·d^(-1)),and low-,medium-,and high-dose (1.5,3,6 g·kg^(-1)·d^(-1),respectively) HLJDT groups,and 8 C57BL/6 mice were taken as the normal group.After 45 days of continuous administration,Morris water maze test was conducted,and the organ indexes were calculated.The morphological structure of cerebral vascular endothelial cells in mice was observed under a transmission electron microscope.Western blot was employed to measure the protein levels of APP,HIF-1α,VEGF,VEGFA,and brain-derived neurotrophic factor (BDNF) in the hippocampus.The mRNA levels of APP,HIF-1α,and VEGF were determined by real-time fluorescence quantitative polymerase chain reaction(Real-time PCR).Result:Compared with the normal group,the model group showed prolonged escape latency(P<0.05),reduced distance and time around the target platform (P<0.05),decrease brain and spleen indexes(P<0.05),vascular endothelial cells with karyopyknosis and not abundant cytoplasm,up-regulated protein levels of APP,HIF-1α,VEGF,and VEGFA (P<0.05),down-regulated protein level of BDNF (P<0.05),and up-regulated mRNA levels of APP,HIF-1α,and VEGF (P<0.05) in the hippocampus.Compared with the model group,high-dose HLJDT shortened the escape latency (P<0.05),increased the distance and time around the target platform (P<0.05),raised the brain and spleen indexes (P<0.05),repaired the organelles of vascular endothelial cells,down-regulated the protein levels of APP,HIF-1α,VEGF,and VEGFA (P<0.05),up-regulated the protein level of BDNF (P<0.05),and down-regulated the mRNA levels of APP,HIF-1α,and VEGF (P<0.05) in the hippocampus.Conclusion:HLJDT can improve the learning and memory abilities of mice by redu

关 键 词：黄连解毒汤 淀粉样前体蛋白(APP)/早老素1(PS1)双转基因小鼠 缺氧诱导因子-1α(HIF-1α) 血管内皮生长因子(VEGF) 

分 类 号：R2-0[医药卫生—中医学] R22R285.5R289R33