Nitazoxanide, an anti-parasitic drug, efficiently ameliorates learning and memory impairments in AD model mice.
Acta Pharmacol Sin
; 40(10): 1279-1291, 2019 Oct.
Article
en En
| MEDLINE
| ID: mdl-31000769
The pathogenesis of Alzheimer's disease (AD) is characterized by both accumulation of ß-amyloid (Aß) plaque and formation of neurofibrillary tangles in the brain. Recent evidence shows that autophagy activation may potently promote intracellular Aß 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 Aß 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/GSK3ß 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 Aß 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tiazoles
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Péptidos beta-Amiloides
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Modelos Animales de Enfermedad
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Enfermedad de Alzheimer
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Aprendizaje
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Trastornos de la Memoria
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Antiparasitarios
Límite:
Animals
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Humans
Idioma:
En
Revista:
Acta Pharmacol Sin
Asunto de la revista:
FARMACOLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Estados Unidos