Lancemaside A inhibits microglial activation via modulation of JNK signaling pathway.
Microglial activation plays an important role in neurodegenerative diseases. Thus, controlling microglial activation is considered to be a promising therapeutic target for neurodegenerative diseases. In the present study, we found that lancemaside A, a triterpenoid saponin isolated from Codonopsislanceolata, inhibited iNOS and proinflammatory cytokines in LPS-stimulated BV2 microglial cells. By analyzing molecular mechanisms underlying the anti-inflammatory effects of lancemaside A, we found that lancemaside A selectively inhibited LPS-induced JNK phosphorylation among the three types of MAP kinases. A JNK-specific inhibitor, SP600125, like lancemaside A, significantly inhibited not only NO, TNF-α, and IL-6 productions, but also NF-κB and AP-1 activities, suggesting that JNK inhibition is largely involved in the anti-inflammatory mechanism of lancemaside A. Interestingly, both the lancemaside A and SP600125 inhibited ROS production by suppressing the expression and/or phosphorylation of NADPH oxidase subunit proteins, such as p47(phox), p67(phox), and gp91(phox). The antioxidant effects of lancemaside A and SP600125 appear to be related with an increase of hemeoxygenase-1 expression by both agents. Finally, we demonstrated the neuroprotective effects of lancemaside A and SP600125 in microglia-neuron coculture systems. Collectively, our data suggest that JNK pathway plays a key role mediating anti-inflammatory effects of lancemaside A in LPS-stimulated microglia.
Department of Molecular Medicine, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.
Yeon-Hui
YH
Jeong
Ji-Sun
JS
Jung
Thi Kim Van
TK
Le
Dong-Hyun
DH
Kim
Hee-Sun
HS
Kim
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D000093242:Interleukin-6 Inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II; D012503:Saponins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C533150:lancemaside A; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse