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

• Published in: International journal of molecular sciences 2020-03, Vol.21 (7), p.2319
• Main Authors: Do, Ha Thi Thu, Bui, Bich Phuong, Sim, Seongrak, Jung, Jae-Kyung, Lee, Heesoon, Cho, Jungsook
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; c-Jun protein; Cell adhesion & migration; Cell Movement - drug effects; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytokines; Cytokines - metabolism; Cytotoxicity; Extracellular signal-regulated kinase; Inflammation; Inflammation Mediators - metabolism; Inhibitory Concentration 50; Interleukin 10; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Isoquinolines - chemistry; Isoquinolines - pharmacology; JNK protein; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; MAP kinase; MAP Kinase Signaling System - drug effects; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Mitogen-Activated Protein Kinases - metabolism; Neurodegeneration; Neurodegenerative Diseases - metabolism; NF-kappa B - metabolism; NF-κB protein; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Nuclear transport; Phosphorylation; Phosphorylation - drug effects; Signal Transduction - drug effects; Transcription factors; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Wound Healing - drug effects
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21072319

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 -(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.