Antifungal drug miconazole ameliorated memory deficits in a mouse model of LPS-induced memory loss through targeting iNOS

Alzheimer's disease (AD) is closely related to neuroinflammation, and the increase in inflammatory cytokine generation and inducible nitric oxide synthase (iNOS) expression in the brain of a patient with AD is well known. Excessive cytokines can stimulate iNOS in microglia and astroglia and ove...

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Bibliographic Details
Published in:Cell death & disease 2020-08, Vol.11 (8), p.623, Article 623
Main Authors: Yeo, In Jun, Yun, Jaesuk, Son, Dong Ju, Han, Sang-Bae, Hong, Jin Tae
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animals
Antifungal agents
Antifungal Agents - pharmacology
Antifungal Agents - therapeutic use
Astrocytes
Astrocytes - drug effects
Astrocytes - metabolism
Brain - pathology
Cell Nucleus - drug effects
Cell Nucleus - metabolism
Cells, Cultured
Cognitive ability
Cyclooxygenase-2
Cytokines
Cytokines - biosynthesis
Disease Models, Animal
Inflammation
Inflammation - complications
Inflammation - pathology
Lipopolysaccharides
Male
Memory
Memory Disorders - complications
Memory Disorders - drug therapy
Memory Disorders - enzymology
Mice, Inbred C57BL
Miconazole
Miconazole - pharmacology
Miconazole - therapeutic use
Microglia
Microglia - drug effects
Microglia - metabolism
Neurodegenerative diseases
NF-KappaB Inhibitor alpha - metabolism
Nitric oxide
Nitric Oxide Synthase Type II - antagonists & inhibitors
Nitric Oxide Synthase Type II - metabolism
Nitric-oxide synthase
Phosphorylation - drug effects
Protein Subunits - metabolism
Protein Transport - drug effects
Rats
Rodents
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Summary:Alzheimer's disease (AD) is closely related to neuroinflammation, and the increase in inflammatory cytokine generation and inducible nitric oxide synthase (iNOS) expression in the brain of a patient with AD is well known. Excessive cytokines can stimulate iNOS in microglia and astroglia and overproduce nitric oxide, which can be toxic to neurons. The disease-gene-drug network analysis based on the GWAS/OMIM/DEG records showed that miconazole (MCZ) affected AD through interactions with NOS. Inhibiting iNOS can reduce neuroinflammation, thus preventing AD progression. To investigate the prophylactic role of antifungal agent in the AD development, a lipopolysaccharide-induced memory disorder mouse model was used, and cognitive function was assessed by Morris water maze test and passive avoidance test. MCZ treatment significantly attenuated cognitive impairment, suppressed iNOS and cyclooxygenase-2 expression, and activation of astrocyte and microglial BV2 cells, as well as reduced cytokine levels in the brains and lipopolysaccharide-treated astrocytes and microglia BV2 cells. In further mechanism studies, Pull-down assay and iNOS luciferase activity data showed that MCZ binds to iNOS and inhibited transcriptional activity. Our results suggest that MCZ is useful for ameliorating the neuroinflammation-mediated AD progression by blocking iNOS expression.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-020-2619-5