Anti-Inflammatory Effects of alpha-Galactosylceramide Analogs in Activated Microglia : Involvement of the p38 MAPK Signaling Pathway
- 주제(키워드) 1 o (alpha galactopyranosyl) 2 hexacosanoylamino 1 , 3 , 4 octadecanetriol , 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole , alpha galactosylceramide , cyclooxygenase 2 , immunoglobulin enhancer binding protein , inducible nitric oxide synthase , interleukin 1beta , interleukin 6 , messenger RNA , mitogen activated protein kinase p38 , nitric oxide , transcription factor AP 1 , tumor necrosis factor alpha , antiinflammatory activity , article , cell activation , controlled study , COX 2 gene , DNA binding , drug structure , enzyme phosphorylation , gene expression regulation , iNOS gene , Interleukin 1beta gene , interleukin 6 gene , microglia , reverse transcription polymerase chain reaction , signal transduction , structure activity relation , transcription regulation
- 등재 SCIE, SCOPUS
- 발행기관 PUBLIC LIBRARY SCIENCE
- 발행년도 2014
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000091046
- 본문언어 영어
- Published As http://dx.doi.org/10.1371/journal.pone.0087030
초록/요약
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 alpha-galactosylceramide (alpha-GalCer) analogs to exert anti-inflammatory effects in activated microglia. We performed biological evaluations of 25 alpha-GalCer analogs and observed an interesting preliminary structure-activity relationship in their inhibitory influence on NO release and TNF-alpha 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-1 beta, and IL-6 at the mRNA level and the expression of TNF-alpha at the post-transcriptional level. In addition, both 4d and 4e inhibited LPS-induced DNA binding activities of NF-kappa B 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-alpha production but also on the DNA binding activities of NF-kB 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-kappa B and AP-1 activities.
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