文献类型：期刊文献

中文题名：Nitazoxanide,an anti-parasitic drug,efficiently ameliorates learning and memory impairments in AD model mice

作者：Lei Fan[1,2];Xiao-xia Qiu[3];Zhi-yuan Zhu[2];Jian-lu Lv[4];Jian Lu[4];Fei Mao[3];Jin Zhu[3];Jia-ying Wang[4];Xiao-wei Guan[4];Jing Chen[1,2];Jin Ren[1,2];Ji-ming Ye[5];Yong-hua Zhao[6];Jian Li[3];Xu Shen[1,3,4]

机构：[1]Center for Drug Safety Evaluation and Research,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;[2]University of Chinese Academy of Sciences,Beijing 100049,China;[3]Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China;[4]School of Medicine and Life Sciences,Nanjing University of Chinese Medicine,Nanjing 210023,China;[5]School of Health and Biomedical Sciences,RMIT University,PO Box 71,VIC 3083,Australia;[6]Institute of Chinese Medical Sciences,University of Macao,Macao,China

年份：2019

卷号：40

期号：10

起止页码：1279

中文期刊名：Acta Pharmacologica Sinica

外文期刊名：中国药理学报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2019_2020】；PubMed;

基金：This work was supported by the National Natural Science Foundation of China(grant number 81473141),NSFC-TRF collaboration projects(grant number NSFC81561148011);the Key Laboratory of Receptor Research of the Chinese Academy of Sciences(grant number SIMM1606YZZ-04);Personalized Medicines:Molecular Signature-based Drug Discovery and Development,Strategic Priority Research Program of the Chinese Academy of Sciences(grant number XDA12040303);the Priority Academic Program Development of Jiangsu Higher Education Institutions(Integration of Chinese and Western Medicine).

语种：英文

中文关键词：Alzheimer's;disease;nitazoxanide;autophagy;inflammation;APP/PS1;transgenic;mice

摘要：The pathogenesis of Alzheimer's disease(AD)is characterized by both accumulation ofβ-amyloid(AB)plaque and formation of neurofirillary tangles in the brain.Recent evidence shows that autophagy activation may potently promote intraellular Aβclearance.Thus targeting autophagy becomes a promising strategy for discovery of drug leads against AD.In the present study,we established a platform to discover autophagy stimulator and screened the lab in-house FDA-approved drug library.We found thatanti-parasitic drug nitazoxanide(NTZ)was an autophagy activator and could efficiently improve learning and memory impairmentsin APP/PS1 transgenic mice.In BV2 cells and primary cortical astrocytes,NTZ stimulated autophagy and promoted Aβclearance by inhibiting both P12K/AKT/mTOR/ULK1 and NQO1/mTOR/ULK1 signaling pathways;NTZ treatment attenuated LPS-induced inflammation by inhibiting PI3K/AKT/IKB/NFKB signaling.In SH-SY5Y cells and primary cortical neurons,NTZ treatment restrained tau hyperphosphorylation through inhibition of PI3K/AKT/GSK3βpathway.The beneficial effects and related signaling mechanisms from the in vitro studies were also observed in APP/PS1 transgenic mice following administration of NTZ(90 mg·kg^-1d,ig)for100 days.Furthermore,NTZ administration decreased Aβlevel and senile plaque formation in the hippocampus and cerebral cortexof APP/PS1 transgenic mice,and improved learning and memory impairments in Morris water maze assay.In conclusion,our results highlight the potential of NTZ in the treatment of AD.