Inhibition of inflammatory mediators and cell migration by 1,2,3,4-tetrahydroquinoline derivatives in LPS-stimulated BV2 microglial cells via suppression of NF-kappa B and JNK pathway

Abstract

Novel 1,2,3,4-tetrahydroquinoline derivatives with N-alkanoyl, N-benzoyl, or chlorobenzoyl substituents were designed and synthesized to inhibit nuclear factor-kappa B (NF-kappa B) known to be involved in the regulation of many immune and inflammatory responses. These compounds have been previously reported to inhibit NF-kappa B transcriptional activity in Raw 267.4 macrophage cells and exhibit cytotoxicities to several human cancer cell lines (Jo et al., ACS Med. Chem. Lett. 7 (2016) 385-390). Accumulating evidence indicated that NF-kappa B is also involved in neuroinflammation implicated in many neurodegenerative diseases. Thus, the present study investigated effects of 1,2,3,4-tetrahydroquinoline derivatives on LPS-stimulated inflammatory mediators and cell migration using BV2 microglial cells as a model. We found that seven compounds tested in this study inhibited LPS-induced pro-inflammatory mediators including interleukin-6, tumor necrosis factor-a, and nitric oxide in concentration-dependent manners. Among these compounds, ELC-D-2 exhibited the most potent inhibition without showing significant cytotoxicity. We also found that ELC-D-2 attenuated levels of LPS-induced inducible nitric oxide synthase and cyclooxygenase-2. Moreover, ELC-D-2 inhibited nuclear translocation of NF-xB by suppressing inhibitor of kappa B alpha phosphorylation. Furthermore, ELC-D-2 inhibited LPS-induced activation of cJun N-terminal kinase (JNK), which was associated with suppression of inflammatory mediators and migration of LPS-treated BV2 cells. Collectively, our findings demonstrate that ELC-D-2 inhibits LPS-induced pro-inflammatory mediators and cell migration by suppressing NF-kappa B translocation and JNK phosphorylation in BV2 microglial cells. These results suggest that ELC-D-2 might have a beneficial impact on various brain disorders in which neuroinflammation involving microglial activation plays a crucial role in the pathogenesis of these diseases.