文献类型：期刊文献

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

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

机构：[1]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China;[2]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[3]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[4]Nanjing Univ Chinese Med, Sch Med & Life Sci, Nanjing 210023, Jiangsu, Peoples R China;[5]RMIT Univ, Sch Hlth & Biomed Sci, POB 71, Melbourne, Vic 3083, Australia;[6]Univ Macau, Inst Chinese Med Sci, Macau, Peoples R China

年份：2019

卷号：40

期号：10

起止页码：1279

外文期刊名：ACTA PHARMACOLOGICA SINICA

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000488273100003)】；

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) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine).

语种：英文

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

摘要：The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of beta-amyloid (A beta) plaque and formation of neurofibrillary tangles in the brain. Recent evidence shows that autophagy activation may potently promote intracellular A beta clearance. 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 that anti-parasitic drug nitazoxanide (NTZ) was an autophagy activator and could efficiently improve learning and memory impairments in APP/PS1 transgenic mice. In BV2 cells and primary cortical astrocytes, NTZ stimulated autophagy and promoted A beta clearance by inhibiting both PI3K/AKT/mTOR/ULK1 and NQO1/mTOR/ULK1 signaling pathways; NTZ treatment attenuated LPS-induced inflammation by inhibiting PI3K/AKT/I.B/NF.B signaling. In SH-SY5Y cells and primary cortical neurons, NTZ treatment restrained tau hyperphosphorylation through inhibition of PI3K/AKT/GSK3 beta pathway. 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(-1).d(-1), ig) for 100 days. Furthermore, NTZ administration decreased A beta level and senile plaque formation in the hippocampus and cerebral cortex of 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.