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Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice
Lei Fan1,2; Xiao-xia Qiu3; Zhi-yuan Zhu2; Jian-lu Lv4; Jian Lu4; Fei Mao3; Jin Zhu3; Jia-ying Wang4; Xiao-wei Guan4; Jing Chen1,2; Jin Ren1,2; Ji-ming Ye5; Yong-hua Zhao6; Jian Li7; Xu Shen8,9,10
2019-10
Source PublicationACTA PHARMACOLOGICA SINICA
ISSN1671-4083
Volume40Issue:10Pages:1279-1291
Abstract

The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of β-amyloid (Aβ) plaque and formation of neurofibrillary tangles in the brain. Recent evidence shows that autophagy activation may potently promote intracellular Aβ 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 Aβ clearance by inhibiting both PI3K/AKT/mTOR/ULK1 and NQO1/mTOR/ULK1 signaling pathways; NTZ treatment attenuated LPS-induced inflammation by inhibiting PI3K/AKT/IκB/NFκB signaling. In SH-SY5Y cells and primary cortical neurons, NTZ treatment restrained tau hyperphosphorylation through inhibition of PI3K/AKT/GSK3β 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 Aβ 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.

KeywordApp/ps1 Transgenic Mice Alzheimer’s Disease Autophagy Inflammation Nitazoxanide
DOI10.1038/s41401-019-0220-1
Indexed BySCI
Language英语
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS IDWOS:000488273100003
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Cited Times [WOS]:2   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.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 Macau, Macau, China
7.hanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
8.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
9.University of Chinese Academy of Sciences, Beijing, 100049, China
10.School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, China
Recommended Citation
GB/T 7714
Lei Fan,Xiao-xia Qiu,Zhi-yuan Zhu,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 Lei Fan.,Xiao-xia Qiu.,Zhi-yuan Zhu.,Jian-lu Lv.,Jian Lu.,...&Xu Shen.(2019).Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice.ACTA PHARMACOLOGICA SINICA,40(10),1279-1291.
MLA Lei Fan,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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