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

ABSTRACT: The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of ?-amyloid (A?) plaque and formation of neurofibrillary tangles in the brain. Recent evidence shows that autophagy activation may potently promote intracellular A? 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? 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? 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? 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.

SUBMITTER: Fan L

PROVIDER: S-EPMC6786387 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Fan Lei L Qiu Xiao-Xia XX Zhu Zhi-Yuan ZY Lv Jian-Lu JL Lu Jian J Mao Fei F Zhu Jin J Wang Jia-Ying JY Guan Xiao-Wei XW Chen Jing J Ren Jin J Ye Ji-Ming JM Zhao Yong-Hua YH Li Jian J Shen Xu X

Acta pharmacologica Sinica 20190418 10

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 ...[more]

PMID: 31000769

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Project description:BackgroundTo evaluate the effect of Isorhynchophylline (IRN) on the learning and memory impairments induced by aluminum chloride (AlCl3) in mice.MethodsFifty male Balb-c mice (4-month-old) were randomly divided into five groups: control, AlCl3 plus vehicle, AlCl3 plus IRN (20 mg/kg), AlCl3 plus IRN (40 mg/kg) and AlCl3 plus donepezil (5 mg/kg). Learning and memory impairments were induced in mice by subcutaneously injecting with AlCl3 (50 mg/kg) once a day for 8 consecutive weeks. At the same time, mice were intragastrically given vehicle or IRN (20 and 40 mg/kg) or donepezil (5 mg/kg) 30 min before each AlCl3 injection. The spatial learning and memory function was assessed using radial arm maze. After sacrificed, the parameters of oxidative stress and cholinergic system in the brain tissues were examined with ELISA kits. Moreover, the expression of nuclear factor kappa B (NF-κB) signaling pathway was analyzed with western blotting.ResultsThe results showed that treatment with IRN could significantly ameliorate the cognitive deficits induced by AlCl3 in mice. In addition, treatment with IRN was found to reduce the level of malondialdehyde, enhance the activities of superoxide dismutases and catalase, increase the level of glutathione, and markedly inhibit the activity of acetylcholinesterase (AChE) in the brain tissues of the AlCl3-treated mice. Moreover, IRN significantly suppressed the phosphorylation of NF-κB p65 and IκBα in the brain tissues of AlCl3-treated mice. However, IRN did not show significant effect on the activity of butyrylcholinesterase.ConclusionOur findings demonstrated for the first time that IRN could alleviate learning and memory impairments induced by AlCl3 in mice. The neuroprotective effect of IRN against AlCl3-induced AD is probably mediated, at least in part, through inhibiting the AChE activity and reducing the oxidative damage of brain tissue via suppress the NF-κB signaling pathway. These results contributed to a better understanding of the in vivo anti-AD mechanism of IRN. It was concluded that IRN could protect the learning and memory function.

Dataset Information

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

Publications

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

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