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

   
@article{APS10033,
	author = {Lei Fan and Xiao-xia Qiu and Zhi-yuan Zhu and Jian-lu Lv and Jian Lu and Fei Mao and Jin Zhu and Jia-ying Wang and Xiao-wei Guan and Jing Chen and Jin Ren and Ji-ming Ye and Yong-hua Zhao and Jian Li and Xu Shen},
	title = {Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice},
	journal = {Acta Pharmacologica Sinica},
	volume = {40},
	number = {10},
	year = {2019},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10033}
}