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

Authors: 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 Li3, Xu Shen1,2,4
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 Macau, Macau, China
Correspondence to: Jian Li:, Xu Shen:,
DOI: 10.1038/s41401-019-0220-1
Received: 20 July 2018
Accepted: 16 January 2019
Advance online: 18 April 2019


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.
Keywords: Alzheimer’s disease; nitazoxanide; autophagy; inflammation; APP/PS1 transgenic mice

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