四种开窍药对APP/PS1小鼠的药效学对比研究及对Aβ/BACE1的影响

Comparative study on pharmacology of four kinds of Kaiqiao drugs on APP/PS1 mice and their effects on A β/BACE1

目的探讨4种开窍药对APP/PS1双转基因小鼠的药效学及对Aβ/BACE1的影响。方法将80只APP/PS1双转基因小鼠随机分为8组,雌雄各半,每组10只:模型组、β-细辛醚低、中、高剂量组(7.5mg/kg, 15mg/kg, 30mg/kg)、苏合香组(8.6mg/kg)、麝香酮组(1.73mg/kg)、冰片组(10.8mg/kg)、多奈哌齐组(1mg/kg)。另设正常组,取APP/PS1基因型阴性小鼠10只。各组灌胃给药,1次/d,给药30d。模型组和正常组用等体积的蒸馏水代替。末次给药1h后,先将各组小鼠进行行为学检测(水迷宫实验、避暗实验、跳台实验),实验结束后,取小鼠海马及前额叶检测药效学指标APP、PS1、Aβ及AD指标BACE1、Syn1,Elisa法检测药效学指标脑组织及血清乙酰胆碱(Ach)。结果水迷宫实验中,模型组比正常组游泳时间显著延长,错误盲区数显著增加;与模型组比较,各用药组的游泳时间缩短,错误盲区数显著减少。避暗实验中,模型组潜伏期较正常组显著缩短;与模型组比较,各用药组潜伏期延长,错误次数减少。跳台实验中,模型组潜伏期较正常组显著缩短;与模型组比较,各用药组潜伏期延长。各用药组脑组织及血清Ach增加,APP、PS1、Aβ、BACE1表达量减少,β-细辛醚可提高Syn1表达,多奈哌齐未见明显变化,苏合香、麝香酮、冰片减少Syn1表达。结论醒脑开窍药β-细辛醚、苏合香、麝香酮、冰片均具有改善AD小鼠学习记忆力,减少APP、PS1、Aβ、BACE1表达,增加Ach表达的作用。

Objective To observe the pharmacology of four kinds of resuscitation drugs on APP/PS1 double transgenic mice and their effects on Aβ/BACE1.Methods 80 APP/PS1 double transgenic mice,male in half,were randomly divided into model group,low,middle and high dose ofβ-asarone(at the dose of 7.5 mg/kg,15 mg/kg,30 mg/kg),storesin(at the dose of 8.6 mg/kg),muscone group(at the dose of 1.73 mg/kg),borneol group(at the dose of 10.8 mg/kg)and Donepezil group(at the dose of 1 mg/kg).In addition,10 APP/PS1 genotype negative mice(male in half)were used as the normal group.The medication groups were administrated with the corresponding drug once a day for 30 days.The model group and the normal group were replaced by the same volume of distilled water.One hour after the last medication,the behavioral tests such as water maze test,step-through test and step-down test were carried out.After that,the hippocampus and prefrontal lobe of mice were taken to detect the pharmacology(APP,PS1,Aβ)and AD indexes(BACE1,Syn1)by immunohistochemisty,the other brain tissues and blood serum were taken to detect acetylcholine(Ach)by enzyme-linked immunosorbent(ELISA).Results In the water maze experiment,the swimming time in the model group was significantly prolonged than that in the normal group,and the number of error blind spots in the model group was significantly higher than that in the normal group,while the swimming time in each medication group was shorter and the number of error blind spots was significantly lower than that in the model group.In the step through test,the latency period of the model group was significantly shorter than that of the normal group,and the latency of each treatment group was longer and the number of errors was less than that of the model group.In the step-down test,the latency period of the model group was significantly shorter than that of the normal group,and the latency period of each medication group was longer than that of the model group.Ach in brain tissue and serum of each treatment group increased,while the expression of APP,PS1,Aβand BACE1 decreased.β-asarone could increase the expression of Syn1,but there was no significant change in Donepezil.Storesin,muscone and borneol decreased the expression of Syn1.Conclusionβ-asarone,Storesin,muscone and borneol have an effect on improving the learning and memory of APP/PS1 double transgenic mice,reducing the expression of APP,PS1,Aβand BACE1,and increasing the expression of Ach.