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

Authors:
Lei Fan
Lei Fan
Jiangsu Province Hospital
China
Zhi-Yuan Zhu
Zhi-Yuan Zhu
From the CAS Key Laboratory of Receptor Research
Jian Lu
Jian Lu
Biological Physics Laboratory
China
Fei Mao
Fei Mao
Jiangsu University
China
Jin Zhu
Jin Zhu
School of Chemistry and Chemical Engineering
United Kingdom
Jia-Ying Wang
Jia-Ying Wang
College of Veterinary Medicine
China

Acta Pharmacol Sin 2019 Apr 18. Epub 2019 Apr 18.

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.

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·d, 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.

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http://dx.doi.org/10.1038/s41401-019-0220-1DOI Listing
April 2019

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References

(Supplied by CrossRef)
Article in Neurology
G McKhann et al.
Neurology 1984
Article in J Med Chem
D Oehlrich et al.
J Med Chem 2011
Article in J Neurochem
SF Lichtenthaler et al.
J Neurochem 2011
Article in J Biol Chem
F Jeppsson et al.
J Biol Chem 2012
Article in Mini Rev Med Chem
SN Bukhari et al.
Mini Rev Med Chem 2015
Article in J Am Med Dir Assoc
RM Sterner et al.
J Am Med Dir Assoc 2016
Article in N Engl J Med
RS Doody et al.
N Engl J Med 2013
Article in Genes Dev
N Mizushima et al.
Genes Dev 2007
Article in Essays Biochem
B Carroll et al.
Essays Biochem 2013
Article in Turk J Med Sci
MC Kizilarslanoglu et al.
Turk J Med Sci 2015
Article in Biochem Soc Trans
Y Wang et al.
Biochem Soc Trans 2012

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