Anti-Inflammatory Effects of α-Galactosylceramide Analogs in Activated Microglia: Involvement of the p38 MAPK Signaling Pathway

Abstract

Microglial activation plays a pivotal role in the development and progression of neurodegenerative diseases. Thus, anti-inflammatory agents that control microglial activation can serve as potential therapeutic agents for neurodegenerative diseases. Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 α-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-α production in LPS-stimulated BV2 microglial cells. After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis. We confirmed that 4d and 4e regulate the expression of iNOS, COX-2, IL-1β, and IL-6 at the mRNA level and the expression of TNF-α at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-κB and AP-1 and phosphorylation of p38 MAPK without affecting other MAP kinases. When we examined the anti-inflammatory effect of a p38 MAPK-specific inhibitor, SB203580, on microglial activation, we observed an identical inhibitory pattern as that of 4d and 4e, not only on NO and TNF-α production but also on the DNA binding activities of NF-κB and AP-1. Taken together, these results suggest that p38 MAPK plays an important role in the anti-inflammatory effects of 4d and 4e via the modulation of NF-κB and AP-1 activities.

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

“…HSR1101 exerted significant inhibition of the phosphorylation of all three types of MAPKs (Figure 7). In accordance with these findings and previous reports [20,[28][29][30], U0126, SP600125, and SB203580, the specific inhibitors of MEK1/2, JNK, and p38 MAPK, respectively, suppressed the LPS-induced production of IL-6, TNF-α, and NO (data not shown). Moreover, LPS-induced cell migration was also reduced by these specific MAPK inhibitors (Figure 8).…”

“…To elucidate the involvement of MAPKs in the inhibition of pro-inflammatory mediators by HSR1101, we investigated the effects of MAPK inhibitors on the production of pro-inflammatory mediators in LPS-treated BV2 cells. In consistence with the findings reported previously [20,[28][29][30], we also observed in our study that U0126, SP600125 and SB203580, the specific inhibitors of MEK1/2 (a type of MAPK/ERK kinase), JNK and p38 MAPK, respectively, noticeably inhibited LPS-promoted production of IL-6, TNF-α, and NO (data not shown). Furthermore, we found that these MAPK inhibitors significantly attenuated iNOS and COX-2 expression and inhibited nuclear translocation of NF-κB and phosphorylation of IκBα in the LPS-treated BV2 cells (data not shown).…”

“…The roles of MAPKs in the production of LPS-induced pro-inflammatory mediators have been well documented [20,[28][29][30]. To elucidate the involvement of MAPKs in the inhibition of pro-inflammatory mediators by HSR1101, we investigated the effects of MAPK inhibitors on the production of pro-inflammatory mediators in LPS-treated BV2 cells.…”

Tetrandrine Suppresses Lipopolysaccharide-Induced Microglial Activation by Inhibiting NF-κB and ERK Signaling Pathways in BV2 Cells

“…Jeonget al [58] showed that the anti-inflammatory effect of α-galactosylceramide was mediated by the inhibition of p38 MAPK activation in activated BV2 cells. Kim et al [25] showed that floridoside inhibited p38 and ERK 1/2 phosphorylation but not JNK in LPS-stimulated BV2 cells, while Dong et al [59] showed that oxymatrine significantly inhibited all of the MAPKs, including ERK, p38, and JNK in LPS-induced BV2 cells.…”

Anti‐Neuroinflammatory Effect of MC13, a Novel Coumarin Compound From Condiment Murraya, Through Inhibiting Lipopolysaccharide‐Induced TRAF6‐TAK1‐NF‐κB, P38/ERK MAPKS and Jak2‐Stat1/Stat3 Pathways

“…Mitogen‐activated protein kinases (MAPKs), as another major inflammatory signal, are also involved in regulating the expression of several inflammatory genes. Both in vitro and in vivo studies have shown that activation of MAPKs (ERK, JNK, and p38) is necessary for a number of the inflammatory responses to LPS [Lee et al, ; Jeong et al, ; Zhao et al, ]. For example, p38 and JNK MAPKs activities are strongly enhanced in multiple cell types including glial cells, endothelial cells, and as well as mononuclear macrophages by LPS or inflammatory cytokines through increasing their phosphorylation levels, and further accelerate inflammatory responses; moreover, TNF‐α mRNA transport from the nucleus to the cytoplasm could be blocked by ERK inhibitor [Raingeaud et al, ; Dong and Davis, ; Zhi et al, ].…”