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

Jeong YH, Kim Y, Song H, Chung YS, Park SB, Kim HS - PLoS ONE (2014)

Bottom Line: Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia.After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.

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.

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Chemical structures of newly designed α-GalCer analogs.
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pone-0087030-g002: Chemical structures of newly designed α-GalCer analogs.

Mentions: As shown in Figure 2, modifications in the acyl chain of α-GalCer contained four different carboxylic acids, including C25H51CO2H (1, from KRN7000), C23H47CO2H (2, from OCH, a known selective TH2 stimulator), octanoic acid (3, from TH2 selective glycolipid) [27], and 6-phenylhexanoic acid (4, from fatty acyl chain analogs with terminal phenyl group) [28]. Analogs containing 1,2,3-triazole, an isostere of amide bonds, had an identical acyl chain length as KRN7000 (5). In consideration of the biological activities of KRN7000, a representative immunomodulatory compound, we maintained the length of the sphingosine backbone of newly designed α-GalCer analogs as a 14-carbon-equivalent chain (a, c–e), similar to that of KRN7000. We also designed a different type of analog containing a 5-carbon-equivalent chain (b), which is similar to the sphigosine backbone of OCH.


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

Jeong YH, Kim Y, Song H, Chung YS, Park SB, Kim HS - PLoS ONE (2014)

Chemical structures of newly designed α-GalCer analogs.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921125&req=5

pone-0087030-g002: Chemical structures of newly designed α-GalCer analogs.
Mentions: As shown in Figure 2, modifications in the acyl chain of α-GalCer contained four different carboxylic acids, including C25H51CO2H (1, from KRN7000), C23H47CO2H (2, from OCH, a known selective TH2 stimulator), octanoic acid (3, from TH2 selective glycolipid) [27], and 6-phenylhexanoic acid (4, from fatty acyl chain analogs with terminal phenyl group) [28]. Analogs containing 1,2,3-triazole, an isostere of amide bonds, had an identical acyl chain length as KRN7000 (5). In consideration of the biological activities of KRN7000, a representative immunomodulatory compound, we maintained the length of the sphingosine backbone of newly designed α-GalCer analogs as a 14-carbon-equivalent chain (a, c–e), similar to that of KRN7000. We also designed a different type of analog containing a 5-carbon-equivalent chain (b), which is similar to the sphigosine backbone of OCH.

Bottom Line: Here, we designed and synthesized α-galactosylceramide (α-GalCer) analogs to exert anti-inflammatory effects in activated microglia.After identification of 4d and 4e as hit compounds, we further investigated the underlying mechanism of their anti-inflammatory effects using RT-PCR analysis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Global Top5 Research Program, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus