Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: Involvement of the p38 MAPK signaling pathway

Yeon Hui Jeong, Yongju Kim, Heebum Song, Young Sun Chung, Seung Bum Park, Hee Sun Kim

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere87030
JournalPloS one
Volume9
Issue number2
DOIs
Publication statusPublished - 2014 Feb 11
Externally publishedYes

Fingerprint

Galactosylceramides
neuroglia
Microglia
p38 Mitogen-Activated Protein Kinases
anti-inflammatory activity
mitogen-activated protein kinase
Anti-Inflammatory Agents
Transcription Factor AP-1
Neurodegenerative diseases
neurodegenerative diseases
Chemical activation
Neurodegenerative Diseases
anti-inflammatory agents
interleukin-1
DNA
prostaglandin synthase
structure-activity relationships
Phosphorylation
interleukin-6
Structure-Activity Relationship

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia : Involvement of the p38 MAPK signaling pathway. / Jeong, Yeon Hui; Kim, Yongju; Song, Heebum; Chung, Young Sun; Park, Seung Bum; Kim, Hee Sun.

In: PloS one, Vol. 9, No. 2, e87030, 11.02.2014.

Research output: Contribution to journalArticle

Jeong, Yeon Hui ; Kim, Yongju ; Song, Heebum ; Chung, Young Sun ; Park, Seung Bum ; Kim, Hee Sun. / Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia : Involvement of the p38 MAPK signaling pathway. In: PloS one. 2014 ; Vol. 9, No. 2.
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