二苯乙烯苷对不同时程APP转基因拟痴呆小鼠脑内ERK蛋白表达及磷酸化的影响  

Effect of 2,3,5,4′-tetrahydroxy Stilbene-2-O-β-D-glucoside on Activation of ERK in APP Transgenic Model of Alzheimer's Disease

作　　者：张兰[1,2] 邢颖[1] 叶翠飞[1] 李林[1] 董奇[2] 

机构地区：[1]首都医科大学宣武医院药物研究室,教育部神经变性病学重点实验室,北京市100053 [2]北京师范大学认知神经科学与学习研究所,北京市100875

出　　处：《中国康复理论与实践》2009年第8期723-727,共5页Chinese Journal of Rehabilitation Theory and Practice

基　　金：国家自然科学基金项目(No.30701092);北京市自然科学基金项目(No.7072033);北京市新世纪百千万人才工程(2008);国家重点基础研究发展计划-"973"项目(No.G2003CB517104)

摘　　要：目的为探讨细胞信号转导异常在阿尔茨海默病(AD)的作用,以及中药有效成分二苯乙烯苷(TSG)防治AD的药理机制,观察不同时程APP转基因拟痴呆小鼠脑内ERK蛋白的表达和磷酸化改变,以及药物的干预作用。方法拟AD动物模型为4～16月龄APP695V717I转基因小鼠。4月龄起灌胃给予TSG6个月。另一批未处理的APP转基因小鼠饲养至10月龄开始灌胃给予TSG6个月。同背景同月龄C57BL/6J小鼠为正常对照组。细胞外信号调节激酶1/2(ERK1/2)蛋白的表达和磷酸化改变检测应用Western blotting。结果早期4月龄APP转基因小鼠海马/皮层被激活的磷酸化ERK1/2蛋白(p-ERK1/2)与对照组相比已明显降低;10月龄APP转基因小鼠皮层p-ERK蛋白表达进一步降低,而海马p-ERK蛋白表达与对照组相比虽显著降低但差异已明显减小;TSG各剂量组均能明显提高海马/皮层p-ERK蛋白表达;16月龄APP转基因小鼠海马/皮层p-ERK蛋白表达与对照组相比均明显升高,TSG给药组能一定程度地减少p-ERK蛋白表达的增高。总的ERK1/2蛋白表达在4、10、16月龄对照组、APP转基因模型组和各给药组小鼠脑内,均无明显变化。结论ERK1/2作为MAPK信号转导通路的重要成分,其蛋白表达在不同时程APP695V717I转基因小鼠脑内无明显改变;但被激活的ERK1/2其磷酸化水平在APP转基因小鼠脑内明显改变,将影响信号转导功能,并进一步导致脑内功能障碍及病理损伤。TSG可调节p-ERK1/2至正常水平,对维持正常的细胞信号转导功能、防治AD等神经退行性疾病具有良好的应用前景。Objective To investigate the deficit of extracellular-signal regulated kinase （ERK）1/2 activation in the different age of Alzheimer＇s disease （AD）-like animal mode1 and the protective effect of 2,3,5,4＇-tetrahydroxy stilbene-2-O-β-D-glucoside（TSG）, which is the main component of Polygonum multiflorum, on ERK activation. Methods A generally accepted animal model of AD -- PDAPPV717I transgenic （Tg） mouse was observed from 4 to 16 months old. Tg mice were randomly divided into 3 model groups（4, 10 and 16 months old mice）and TSG treated （at doses 120 and 240 μmol/kg/d） groups. TSG was administered to some Tg mice with an age range 4--10 months. In untreated 10 months old Tg mice, the TSG was administrated to those falling in the age range 10-16 months. For the control group we adopted the same age and background C57BL/6J mice. The ERK1/2 expression and phospho- rylation were detected by Western blotting. Results In the 4-month-old PDAPPV717I Tg mice, phosphorylation of ERK1/2 decreased significantly in hippocampus and cortex compared with age matched control. In the 10-month-old Tg mice, decrease of ERK1/2 activation was aggravated in cortex but was less in hippoeampus. The treatment of TSG at the doses of 120 and 240 μmol/ kg for 6 months （from the age of 4 to 10 months） significantly up-regulated ERK1/2 activation in rig mice. In the 16-month-old rig mice, over-activation of ERK1/2 occurred in both hippocampus and cortex. The transgenic mice treated by TSG for 6 months （from the age of 10 months to 16 months） showed significant inhibition of over-activation of ERK1/2. Expression of total ERK1/2 showed no difference among control, Tg model and TSG treated groups. Conclusion PDAPPV717I transgenic mice with an age range from 4 to 16 months revealed the time-dependent deficit of ERK1/2 activation. TSG can bring the down or over activation of ERK1/2 into normal. Because ERK1/2 activation plays the crucial role in cellular signal transduction and learning-memory ability, TSG may hav

关 键 词：阿尔茨海默病 APP转基因小鼠 细胞外信号调节激酶1/2(ERK1/2) 信号转导 二苯乙烯苷 

分 类 号：R965[医药卫生—药理学]