Anti-Inflammatory and Anti-Migratory Activities of Isoquinoline-1-Carboxamide Derivatives in LPS-Treated BV2 Microglial Cells via Inhibition of MAPKs/NF-κB Pathway

Abstract

Eleven novel isoquinoline-1-carboxamides (HSR1101~1111) were synthesized and evaluated for their effects on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators and cell migration in BV2 microglial cells. Three compounds (HSR1101~1103) exhibited the most potent suppression of LPS-induced pro-inflammatory mediators, including interleukin (IL)-6, tumor necrosis factor-alpha, and nitric oxide (NO), without significant cytotoxicity. Among them, only N-(2-hydroxyphenyl) isoquinoline-1-carboxamide (HSR1101) was found to reverse LPS-suppressed anti-inflammatory cytokine IL-10, so it was selected for further characterization. HSR1101 attenuated LPS-induced expression of inducible NO synthase and cyclooxygenase-2. Particularly, HSR1101 abated LPS-induced nuclear translocation of NF-κB through inhibition of IκB phosphorylation. Furthermore, HSR1101 inhibited LPS-induced cell migration and phosphorylation of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 MAPK. The specific MAPK inhibitors, U0126, SP600125, and SB203580, suppressed LPS-stimulated pro-inflammatory mediators, cell migration, and NF-κB nuclear translocation, indicating that MAPKs may be the upstream kinase of NF-κB signaling. Collectively, these results demonstrate that HSR1101 is a potent and promising compound suppressing LPS-induced inflammation and cell migration in BV2 microglial cells, and that inhibition of the MAPKs/NF-κB pathway mediates its anti-inflammatory and anti-migratory effects. Based on our findings, HSR1101 may have beneficial impacts on various neurodegenerative disorders associated with neuroinflammation and microglial activation.

Keywords

• isoquinoline-1-carboxamide
• nuclear factor-kappa B (NF-κB)
• mitogen-activated protein kinases (MAPKs)
• BV2 microglial cells
• intracellular signaling
• neuroinflammation