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

文献类型：期刊论文

作者Fan, Lei3,4; Qiu, Xiao-xia2; Zhu, Zhi-yuan3; Lv, Jian-lu5; Lu, Jian5; Mao, Fei2; Zhu, Jin2; Wang, Jia-ying5; Guan, Xiao-wei5; Chen, Jing3,4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2019-10-01
卷号40期号:10页码:1279-1291
关键词Alzheimer's disease nitazoxanide autophagy inflammation APP/PS1 transgenic mice
ISSN号1671-4083
DOI10.1038/s41401-019-0220-1
通讯作者Li, Jian(jianli@ecust.edu.cn) ; Shen, Xu(xshen@njucm.edu.cn)
英文摘要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.
WOS关键词ALZHEIMERS-DISEASE ; AMYLOID-BETA ; SIGNALING PATHWAY ; TAU-PROTEIN ; AUTOPHAGY ; ACTIVATION ; NEUROINFLAMMATION ; DEGRADATION ; EXPOSURE ; KINASE
资助项目National Natural Science Foundation of China[81473141] ; NSFC-TRF collaboration projects[NSFC81561148011] ; Key Laboratory of Receptor Research of the Chinese Academy of Sciences[SIMM1606YZZ-04] ; Personalized Medicines: Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040303] ; Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine)
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000488273100003
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/282659]  
专题新药研究国家重点实验室
通讯作者Li, Jian; Shen, Xu
作者单位1.Univ Macau, Inst Chinese Med Sci, Macau, Peoples R China
2.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Med & Life Sci, Nanjing 210023, Jiangsu, Peoples R China
6.RMIT Univ, Sch Hlth & Biomed Sci, POB 71, Melbourne, Vic 3083, Australia
推荐引用方式
GB/T 7714		 Fan, Lei,Qiu, Xiao-xia,Zhu, Zhi-yuan,et al. Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice[J]. ACTA PHARMACOLOGICA SINICA,2019,40(10):1279-1291.
APA Fan, Lei.,Qiu, Xiao-xia.,Zhu, Zhi-yuan.,Lv, Jian-lu.,Lu, Jian.,...&Shen, Xu.(2019).Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice.ACTA PHARMACOLOGICA SINICA,40(10),1279-1291.
MLA Fan, Lei,et al."Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice".ACTA PHARMACOLOGICA SINICA 40.10(2019):1279-1291.

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来源：上海药物研究所

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