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.
Highlights
Neurodegeneration is described as the slow and progressive dysfunction and loss of neurons or axons in the central nervous system (CNS)
The present study aimed to evaluate the effects of the newly synthesized isoquinoline-1-carboxamides on LPS-stimulated inflammation and cell migration in BV2 microglial cells
Simultaneous treatment with LPS and HSR1101 at 30 or 100 μM dramatically decreased the LPS-induced inducible NO synthase (iNOS) and COX-2 expression (Figure 4). These results suggest that the inhibition of iNOS and COX-2 expression by HSR1101 may contribute to its anti-inflammatory effect in LPS-stimulated BV2 cells
Summary
Neurodegeneration is described as the slow and progressive dysfunction and loss of neurons or axons in the central nervous system (CNS). The present study employed LPS-treated BV2 cells, a murine microglial cell line, as a model to evaluate the effects of synthesized isoquinoline-1-carboxamide derivatives on the production of pro-inflammatory mediators and cell migration [17,18]. It is well-recognized that activation of the nuclear factor-kappa B (NF-κB) family plays a critical role in inflammation. Among the eleven tested compounds, N-(2-hydroxyphenyl)isoquinoline-1-carboxamide (HSR1101) potently inhibited LPS-induced production of the pro-inflammatory mediators including IL-6, TNF-α, and NO in BV2 cells. Sci. 2020, 21, x FOR PEER REVIEW InInt.t.JJ..MMool.l.SSccii..22002200,,2211,,2x31F9OR PEER REVIEW
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