3′,4′-Dihydroxyflavonol Attenuates Lipopolysaccharide-Induced Neuroinflammatory Responses of Microglial Cells by Suppressing AKT–mTOR and NF-κB Pathways

Abstract

Microglia-related neuroinflammation contributes to the pathogenesis of a variety of neurodegenerative disorders such as Alzheimer’s disease. The synthetic flavonoid, 3′,4′-dihydroxyflavonol (3,3′,4′-trihydroxyfla-vone), has been shown to protect brain or myocardial ischemia reperfusion-induced cell death and prevent the aggregation of amyloid-β protein, a process that causes progressive neurodegeneration in Alzheimer’s disease. Here, we explored the anti-neuroinflammatory ability of 3′,4′-dihydroxyflavonol in lipopolysaccharide (LPS)-activated MG6 microglial cells. 3′,4′-Dihydroxyflavonol attenuated LPS-induced tumor necrosis factor-α and nitric oxide secretion in MG6 cells. LPS-induced phosphorylation of mammalian target of rapamycin (mTOR), nuclear factor-κB (NF-κB), and protein kinase B (AKT) (which are all associated with the neuroinflammatory response in microglia) were attenuated by 3′,4′-dihydroxyflavonol treatment. Treatment with the mTOR inhibitor, rapamycin, NF-κB inhibitor, caffeic acid phenethyl ester, or AKT inhibitor, LY294002, also attenuated LPS-induced tumor necrosis factor-α and nitric oxide secretion in MG6 cells. LY294002 treatment attenuated LPS-induced phosphorylation of mTOR and NF-κB in MG6 cells. Hence, our study suggests that 3′,4′-dihydroxyflavonol can attenuate the neuroinflammatory response of microglial cells by suppressing the AKT–mTOR and NF-κB pathways.