A Systematic Review Of Traditional Chinese Medicine Combined With Donepezil In The Treatment Of Alzheimer's Disease And Its Effect On Mouse Behavior

Objective:Evaluating the efficacy and safety of traditional Chinese medicine combined with donepezil hydrochloride in the treatment of Alzheimer’s disease by systematic review of clinical trial reports and animal experiment results.Methods:(1)Published literatures in China National Knowledge Infrastructure(CNKI),Wanfang Data Knowledge Service Platform(WANFANG DATA),VIP Resource System(VIP),Chinese Academy of Sciences China Biomedical Literature CD-ROM Database(CBMdisc)4 Chinese databases and Pubmed,The Cochrane Library and Embase other 3 English databases were retrived through computer.The search time is from the starting year of the collection to February 2019.All literatures were screened according to the iclusion and exclusion criteria,and study information was extracted.The included literatures were heterogeneously evaluated by using the Revman 5.3 software provided by the Cochrane Collaboration,and a subgroup analysis was determined based on the results of the heterogeneity evaluation.(2)Using 120 3-month-old APP/PS1/Tau,3×Tg-AD mice,male and female,purchased from the Wilson Laboratory in the United States,raised and reproduced in the barrier animal room of the Institute of Basic Theory of Chinese Medicine,China Academy of Chinese Medical Sciences,while purchasing twenty same months C57BL/6J mice with the same genetic background were used as the normal control group.3×Tg-AD mice were randomly divided into 6 groups according to the random number table,male and female,respectively,include GEPT high dose group,GEPT medium dose group,GEPT low dose group,GEPT medium dose and donepezil hydrochloride named combined group,donepezil hydrochloride group,model group.GEPT 30mg·ml-1,15mg·ml-1,7.5mg·ml-1 were administered to the stomach,and the donepezil hydrochloride group was administered with donepezil hydrochloride 0.092mg·ml-1.The combined group was given GEPT 15mg·ml-1 and donepezil hydrochloride 0.092mg·ml-1,was intragastrically administered.Both the model group and the normal group were given an equal volume of 0.5%CMC.The mice were fed for 4 months from 3-month-old,the behavioral changes of the mice were observed by the morris water maze test at 7-month-old.The collected data was analyzed by using SPSS 20.0 statistical software.Results:(1)In terms of effective rate,the effective rate of Chinese medicine combined with donepezil hydrochloride in AD patients was greater than that of donepezil hydrochloride alone,OR[2.84,95%CI(2.33,3.61),p<0.00001].The subgroup analysis was performed with the MMSE score as the outcome index.At the 2 months of treatment,6 studies(X2=3.36,p=0.50,I2=0%)had good homogeneity,MD[2.97,95%CI(2.42,3.52),p<0.00001],showing that Chinese medicine combined with donepezil hydrochloride was better than donepezil hydrochloride alone.At 3 months of treatment,6 studies(X2=9.115,p=0.10,I2=45%)showed moderate heterogeneity,MD[1.91,95%CI(1.20,2.63),p<0.00001],showing the efficacy of traditional Chinese medicine combined with donepezil hydrochloride was better than that of donepezil hydrochloride alone.At 6 months of treatment,11 studies(X2=27.315,p=0.002,I2=63%),moderate heterogeneity,MD[2.44,95%CI(1.66,3.22),p<0.00001],showing that Chinese medicine combined with donepezil hydrochloride is better than donepezil hydrochloride alone.Subgroup analysis was performed with the ADAS-cog score as the outcome measure.At 2 months of treatment,3 studies(X2=10.01,p=0.007,12=80%)were highly heterogeneous,MD[-7.87,95%CI(-11.69,-4.06),p<0.0001].At 6 months of treatment,8 studies(X2=13.51,p=0.06,I2=48%),mild heterogeneity,MD[-2.36,95%CI(-3.57,-1.15),p=0.0001],showing that Chinese medicine combined with donepezil hydrochloride is better than donepezil hydrochloride alone.Through the meta-analysis of three indicators that evaluated the efficacy of AD,showed that Chinese medicine combined with donepezil hydrochloride treatment of AD was superior to donepezil hydrochloride alone.In terms of safety,12 studies reported adverse reactions,combining the number of adverse reactions(X2=21.32,p=0.03,I2=48%),mild heterogeneity,OR[0.53,95%CI(0.15,1.93),p=0.20].It showed that Chinese medicine combined with donepezil hydrochloride in the treatment of AD doesn’t increase the risk of adverse reactions compared with donepezil hydrochloride alone.(2)In the positioning navigation test and the space exploration test,the male and female are separated.Positioning navigation test,female rats,total swimming distance,on the 1-5th day,the swimming distance of each group of mice decreased as the number of test days increased.There was a significant difference between the model group and the normal group on the 1-4th day.On the 1-4th day,there was a significant difference between the combined group and the model group,suggesting that the learning and memory ability of the combined group was better than that of the model group.The high dose group on the 3-5th day was significantly different from the model group,suggesting that the learning and memory ability of the high dose group was better than that of the model group.However,there was no significant difference between the high-dose group and the combined group(p>0.05).In the space exploration experiment,the female mice and the target quadrant stay time were significantly different between the model group and the normal group.There was a significant difference between the low dose group,the combined group and the model group.There was no difference between the low dose group and the combined group(p>0.05).It is suggested that the low-dose group and the combined group may have a better effect on the exploration ability of female rats.Male rats,the model group was significantly different from the normal group,and the high dose group was significantly different from the model group.It is suggested that the high dose group in male rats may have a better effect on the exploration ability of mice.The water maze test results showed that Chinese medicine combined with donepezil hydrochloride improved the learning and memory ability of female rats.Conclusion:(1)Chinese medicine combined with donepezil hydrochloride in the treatment of AD is superior to donepezil hydrochloride alone in improving cognition,and doesn’t increase the risk of adverse reactions.However,the original literature is biased and the level of evidence is low.(2)Traditional Chinese medicine combined with donepezil hydrochloride improved the learning and memory ability of 7-month-old 3×Tg-AD female mice,and had no obvious effect on male mice,and was superior to donepezil hydrochloride alone.Because of the small sample size,there may be bias.