丁苯酞干预APP/PS1转基因小鼠(阿尔茨海默病模型)的认知功能

N-butylphthalide affects cognitive function of APP/PS1 transgenic mice(Alzheimer's disease model)

背景:β淀粉样蛋白被认为是阿尔茨海默病发病的关键因素,抗脑缺血药物丁苯酞(NBP)是治疗血管性痴呆的一种关键药物。目的:分析丁苯酞治疗APP/PS1转基因小鼠是否参与STEP-ERK-CREB信号通路的机制。方法:SPF级雄性APP/PS1转基因小鼠(阿尔茨海默病模型小鼠)30只,12月龄,购自北京华阜康生物科技股份有限公司;SPF级C57BL/6野生型小鼠10只,购自北京维通利华实验动物技术有限公司。动物分4组,每组10只:C57BL/6野生型小鼠组;APP/PS1组;丁苯酞10 mg/kg组和30 mg/kg组(分别每日灌胃丁苯酞10 mg/kg和丁苯酞30 mg/kg);野生型小鼠组和APP/PS1组小鼠每日灌胃等量植物油。连续灌胃17 d,第9-16天进行行为学实验,在水迷宫训练前40 min给予丁苯酞;第17天处死小鼠,Western-blot检测小鼠皮质STEP61、p ERK1/2、pCREB的蛋白表达。结果与结论:①连续给予10和30 mg/kg丁苯酞药物治疗16 d:可明显改善APP/PS1转基因小鼠Morris水迷宫任务中的空间学习缺陷,减轻其工作记忆障碍;②Western-blot检测显示:丁苯酞部分降低了活化的STEP61蛋白水平,抑制ERK和CREB的磷酸化;③结果说明:丁苯酞对APP/PS1转基因小鼠具有抗β淀粉样蛋白诱导的神经变性和认知功能减退的保护作用,其可能具有治疗阿尔茨海默病的潜力。

BACKGROUND: Amyloid-β protein is a key factor of pathogenesis of Alzheimer’s disease. N-butylphthalide, an anti-cerebral ischemia drug, has been shown to have therapeutic effects in vascular dementia. OBJECTIVE: To investigate whether N-butylphthalide treating APP/PS1 transgenic mice via the SPEP-ERK-CREB signaling pathway. METHODS: Thirty male APP/PS1 transgenic mice(mouse model of Alzheimer’s disease), SPF grade, aged 12 months were provided by Beijing Huafukang Biotechnology Co., Ltd., and 10 C57 BL/6 wild-type mice, SPF grade, were provided by Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The animals were divided into four groups(n=10/group): C57 BL/6 wild-type mice group, APP/PS1 group, and 10 and 30 mg/kg N-butylphthalide groups. The former two groups were given same volume of vegetable oil via gavage, for 17 consecutive days. The behavioral test was performed at 9-16 days. N-butylphthalide was given 40 minutes prior to Morris water maze task. The mice were killed at 17 days, and the proteins levels of STEP61, pERK1/2 and pCREB in brain cortex were detected by western blot assay. RESULTS AND CONCLUSION:(1) Consecutive 16-day 10 and 30 mg/kg N-butylphthalide could significantly improve spatial learning disability and working memory disorder of APP/PS1 transgenic mice in Morris water maze test.(2) N-butylphthalide partly reduced the level of activated STEP61, and inhibited the dephosphorylation of ERK and CREB.(3) These results suggest that N-butylphthalide protects against amyloid-β-induced neurodegeneration and cognitive decline in APP/PS1 transgenic mice, which may be potential for Alzheimer’s disease.