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

doi:10.1038/s41401-019-0220-1

	Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice
	Fan, Lei 3,4; Qiu, Xiao-xia 2; Zhu, Zhi-yuan 3; Lv, Jian-lu 5; Lu, Jian 5; Mao, Fei 2; Zhu, Jin 2; Wang, Jia-ying 5; Guan, Xiao-wei 5; Chen, Jing 3,4
刊名	ACTA PHARMACOLOGICA SINICA
	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
DOI	10.1038/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.
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关键词	ALZHEIMERS-DISEASE ; AMYLOID-BETA ; SIGNALING PATHWAY ; TAU-PROTEIN ; AUTOPHAGY ; ACTIVATION ; NEUROINFLAMMATION ; DEGRADATION ; EXPOSURE ; KINASE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000488273100003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282659]
专题	中国科学院上海药物研究所
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.