Anti-inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide-stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase-1 expression.
Microglia activation plays a pivotal role in neurodegenerative diseases, and thus controlling microglial activation has been suggested as a promising therapeutic strategy for neurodegenerative diseases. In the present study, we showed that ginsenoside Rh1 inhibited inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokine expression in lipopolysaccharide (LPS)-stimulated microglia, while Rh1 increased anti-inflammatory IL-10 and hemeoxygenase-1 (HO-1) expression. Suppression of microglial activation by Rh1 was also observed in the mouse brain following treatment with LPS. Subsequent mechanistic studies revealed that Rh1 inhibited LPS-induced MAPK phosphorylation and nuclear factor-κB (NF-κB)-mediated transcription without affecting NF-κB DNA binding. As the increase of pCREB (cAMP responsive element-binding protein) is known to result in suppression of NF-κB-mediated transcription, we examined whether Rh1 increased pCREB levels. As expected, Rh1 increased pCREB, which was shown to be related to the anti-inflammatory effect of Rh1 because pre-treatment with protein kinase A inhibitors attenuated the Rh1-mediated inhibition of nitric oxide production and the up-regulation of IL-10 and HO-1. Furthermore, treatment of HO-1 shRNA attenuated Rh1-mediated inhibition of nitric oxide and reactive oxygen species production. Through this study, we have demonstrated that protein kinase A and its downstream effector, HO-1, play a critical role in the anti-inflammatory mechanism of Rh1 by modulating pro- and anti-inflammatory molecules in activated microglia.
Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Korea.
Ji-Sun
JS
Jung
Jin A
JA
Shin
Eun-Mi
EM
Park
Jung-Eun
JE
Lee
Young-Sook
YS
Kang
Sung-Won
SW
Min
Dong-Hyun
DH
Kim
Jin-Won
JW
Hyun
Chan-Young
CY
Shin
Hee-Sun
HS
Kim
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D036145:Ginsenosides / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000201:enzymology*; D005894:Panax; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D036145:Ginsenosides; D008070:Lipopolysaccharides; C425564:ginsenoside Rh1; D051547:Heme Oxygenase-1; D017868:Cyclic AMP-Dependent Protein Kinases