Abstract
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.
Highlights
Dementia, an age-related disease, is characterized by difficulties with memory, speaking, problem-solving, and other cognitive abilities[1]
Miconazole improves memory impairment in LPS-treated mice Our results showed that there was some weight loss in early injection days, at day 8 they recovered to normal weight that showed there was no significant difference between control group (Supplementary Fig. 2A); and open-field test result demonstrated daily low-dose LPS injection that had no significant effect on sickness behavior (Supplementary Fig. 2B)
As MCZ could act as an inflammation inhibitory drug, and LPS-induced Alzheimer’s disease (AD) model could be useful for neuroinflammatory AD model, we examined effect of MCZ on memory improving ability in the LPS-induced AD model
Summary
An age-related disease, is characterized by difficulties with memory, speaking, problem-solving, and other cognitive abilities[1]. It is well known that cytokines, chemokines, caspases, nitric oxide (NO), and reactive oxygen species (ROS) cause neuroinflammation and can lead to neurodegenerative diseases[5]. There has been much research illustrating the relationship of iNOS expression and NO generation with neuroinflammation and dementia[6,7]. INOS knockout mice showed improved cognitive ability and multiple pathologies[10,11]. During the course of inflammation, excessive cytokines can stimulate iNOS in microglia and astroglia cells and overproduce nitric oxide, which can lead to neurodegeneration[12,13] Nuclear factor-kappa B (NF-κB) is a transcription factor that influences the levels of several inflammatory genes, such as iNOS and COX-2, as well as Official journal of the Cell Death Differentiation Association
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