title: 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.
authors: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.
authors: Yeon-Hui
authors: YH
authors: Jeong
authors: Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
authors: Yongju
authors: Y
authors: Kim
authors: Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
authors: Heebum
authors: H
authors: Song
authors: Department of Counseling Psychology, Korea Soongsil Cyber University, Seoul, Republic of Korea.
authors: Young Sun
authors: YS
authors: Chung
authors: Department of Chemistry, Seoul National University, Seoul, Republic of Korea ; Department of Biophysics and Chemical Biology/Bio-MAX Institute, Seoul National University, Seoul, Republic of Korea.
authors: Seung Bum
authors: SB
authors: Park
authors: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.
authors: Hee-Sun
authors: HS
authors: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D005699:Galactosylceramides / Q000737:chemistry*; D015971:Gene Expression Regulation, Enzymologic; D007093:Imidazoles / Q000737:chemistry; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D005699:Galactosylceramides; D007093:Imidazoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018808:Transcription Factor AP-1; C493154:alpha-galactosylceramide; C577686:interleukin-6, mouse; D004247:DNA; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580