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

Biol Pharm Bull. 2023;46(7):914-920. doi: 10.1248/bpb.b23-00033.

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'-trihydroxyflavone), 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.

Keywords: 3′,4′-dihydroxyflavonol; mammalian target of rapamycin; microglia; nuclear factor-κB; protein kinase B.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Lipopolysaccharides
  • Mice
  • Microglia / metabolism
  • NF-kappa B* / metabolism
  • Nitric Oxide / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 3',4'-dihydroxyflavonol
  • Lipopolysaccharides
  • NF-kappa B
  • Nitric Oxide
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Tumor Necrosis Factor-alpha