Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity.
Microglia are innate immune cells in the central nervous system. Activation of microglia plays an important role in the processes of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated microglia can produce various proinflammatory cytokines and nitric oxide (NO), which may exert neurotoxic effects. Inhibition of microglia activation may alleviate neurodegeneration under these conditions. To search for the novel therapeutic agents against neuroinflammatory diseases, we have screened a series of flavonoid compounds using a cell-based assay. Our studies showed that fisetin markedly suppressed the production of tumor necrosis factor (TNF)-alpha, NO, and prostaglandin (PG) E2 in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells or primary microglia cultures. Fisetin also inhibited the gene expression of TNF-alpha, interleukin (IL)-1 beta, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) at both mRNA and protein levels. Fisetin significantly suppressed I kappa B degradation, nuclear translocation of NF-kappa B, and phosphorylation of p38 mitogen-activated protein kinase (MAPKs) in the LPS-stimulated BV-2 microglia cells. In addition, fisetin reduced cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in a co-culture system. These results indicate that fisetin has a strong anti-inflammatory activity in brain microglia, and could be a potential therapeutic agent for the treatment of neuroinflammatory diseases.
Zheng
Long Tai
LT
Department of Pharmacology, School of Medicine, Brain Science and Engineering Institute, CMRI, Kyungpook National University, Daegu, Republic of Korea.
Ock
Jiyeon
J
Kwon
Byoung-Mog
BM
Suk
Kyoungho
K
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D053583:Interleukin-1beta / Q000235:genetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005419:Flavonoids; D044948:Flavonols; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C017875:fisetin