Salvianolic acid A suppress lipopolysaccharide-induced NF-κB signaling pathway by targeting IKKβ

• Published in: International immunopharmacology 2011-11, Vol.11 (11), p.1901-1906
• Main Authors: Oh, Kwang-Seok, Oh, Byung Koo, Mun, Jihye, Seo, Ho Won, Lee, Byung Ho
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Caffeic Acids - pharmacokinetics; Cell Line; Cell Survival - drug effects; Cyclooxygenase 2 - metabolism; Dinoprostone - metabolism; Fluorescence Resonance Energy Transfer; I-kappa B Kinase - antagonists & inhibitors; Immunoblotting; IκB kinase β; Lactates - pharmacokinetics; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - enzymology; Macrophages - metabolism; Medical sciences; Mice; Microscopy, Fluorescence; Molecular Structure; Murine macrophage RAW 264.7 cells; NF-kappa B - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitrites - metabolism; Nuclear factor κB; Pharmacology. Drug treatments; Salvianolic acid A
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2011.07.022

Salvianolic acid A, an active compound present in Salvia miltiorrhiza, is a phenolic carboxylic acid derivative, ((2R)-3-(3,4-Dihydroxyphenyl)-2-[(E)-3-[2-[(E)-2-(3,4-dihydroxyphenyl) ethenyl]-3,4-dihydroxyphenyl] prop-2-enoyl]oxypropanoic acid). The present study was performed to investigate the underlying mechanisms of anti-inflammatory effects with salvianolic acid A, specially focused on nuclear factor κB (NF-κB) signaling pathway by targeting the IκB kinase β (IKKβ). The effect of salvianolic acid A for IKKβ activity was analyzed using an immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The underlying mechanisms of salvianolic acid A were examined using lipopolysaccharide (LPS)-stimulated RAW264.7 cells. IKKβ studies based on IMAP-TR-FRET showed that salvianolic acid A possesses a potent IKKβ inhibitory activity with Ki value of 3.63μM in an ATP-noncompetitive manner. Pretreatment with salvianolic acid A (10, 30μM) decreased LPS-induced expression of iNOS and COX-2, thereby inhibiting production of nitric oxide and prostaglandin E2, respectively. In addition, salvianolic acid A (10, 30μM) also attenuated the LPS-induced IκBα phosphorylation and degradation, and NF-κB translocation. These results suggest that salvianolic acid A modulates NF-κB-dependent inflammatory pathways through IKKβ inhibition and these anti-inflammatory effects will aid in understanding the pharmacology and mode of action of salvianolic acid A. ► Mechanism of salvianolic acid A on anti-inflammatory action was investigated. ► Salvianolic acid A showed a potent IKKβ inhibitory activity (IC50: 3.63μM). ► It decreased LPS-induced expression of iNOS and COX-2, and production of NO and PGE2. ► It attenuated LPS-induced IκBα phosphorylation/degradation and NF-κB translocation. ► It modulates NF-κB-dependent inflammatory pathways through IKKβ inhibition.