Anti-inflammatory mechanism of galangin in lipopolysaccharide-stimulated microglia: Critical role of PPAR-gamma signaling pathway

Abstract

Since microglia-associated neuroinflammation plays a pivotal role in the progression of neurodegenerative diseases, controlling microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of galangin (3,5,7-trihydroxyflavone) in microglia and analyzed the underlying molecular mechanisms. Galangin inhibited the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines and enhanced the expression of anti-inflammatory interleukin (IL)-10 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Galangin also suppressed microglial activation and the expression of pro-inflammatory markers in LPS-injected mouse brains. The results of mechanistic studies have shown that galangin inhibited LPS-induced phosphorylation of p38 mitogen activated protein kinase (MAPK), c-jun N-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI3K)/Akt, and nuclear factor (NF)-kappa B activity. On the contrary, galangin increased the activity of transcription factors, such as nuclear factor-E2-related factor 2 (Nrf2), cAMP response element-binding protein (CREB), and peroxisome proliferator-activated receptor (PPAR)-gamma, known to play an anti-inflammatory role. In addition, galangin showed antioxidant effects by suppressing the expression of NADPH oxidase subunits p47(Phox) and gp91(Phox), and by enhancing hemeoxygenase-1. We then investigated whether PPAR-gamma was involved in the anti-inflammatory function of galangin. Pretreatment with a PPAR-gamma antagonist or siRNA significantly blocked galangin-mediated upregulation of IL-10 and attenuated the inhibition of tumor necrosis factor (TNF)-alpha, nitric oxide (NO), and IL-6 in LPS-stimulated microglia. Moreover, the PPAR-gamma antagonist reversed the effects of galangin on NF-kappa B, Nrf2, and CREB. Altogether, our data suggest that PPAR-gamma plays a key role in mediating the anti-inflammatory effects of galangin by modulating the NF-kappa B and Nrf2/CREB signaling pathways. (C) 2017 Elsevier Inc. All rights reserved.