A dopamine-alpha-lipoic acid hybridization compound and its acetylated form inhibit LPS-mediated inflammation

In the present study, we synthesized and evaluated the anti-inflammatory effects of dopamine and alpha-lipoic acid (ALA) hybrid compounds, ALA-dopamine (HBU-199) and its acetylated derivative, ALA-acetyl dopamine (HBU-200), in BV2 microglia and RAW264.7 macrophage cells. HBU-199 and HBU-200 both significantly and dose dependently inhibited LPS-induced nitric oxide (NO) productions, NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 and interleukin-1 beta mRNA expressions and iNOS and COX-2 protein expressions. Furthermore, HBU-199 and HBU-200 protected RAW264.7 cells from activation induced cell death. However, at same concentrations, dopamine or ALA did not inhibit LPS-medialed production of inflammatory molecules and activation induced cell death. HBU-199 and HBU-200 inhibited LPS-induced inhibition of inhibitory kappa-B-alpha (I kappa B-alpha) phosphorylalion and nuclear factor kappa B (NF-kappa B) activation. Furthermore, LPS mediated DNA binding of p65 and p50 to the NF-kappa B binding site of the iNOS promoter was inhibited by HBU-199 and HBU-200, whereas dopamine and ALA did not inhibit LPS induced NF-kappa B activation and I kappa B-alpha phosphorylalion. Moreover, HBU-199 and HBU-200 suppressed LPS stimulated phosphorylalion of Akt. but not glycogen synthase kinase 3 beta. Overall, our data suggest that the ALA-dopamine hybrid compounds down-regulate inflammatory responses via inhibition of NE-kappa B and NF-kappa B-dependent gene expression, suggesting that it is a promising therapeutic agent for both systemic inflammatory diseases and inflammatory diseases of central nervous system. (C) 2014 Elsevier B.V. All rights reserved.