The new diterpene isodojaponin D inhibited LPS-induced microglial activation through NF-kappaB and MAPK signaling pathways.
Neuroinflammation with prolonged microglial activation leads to increased levels of pro-inflammatory mediators and subsequently contributes to neuronal dysfunction and neuronal loss. Therefore, pharmacological suppression of neuroinflammation would theoretically slow the progression of neurodegenerative disease. In this study, we investigated the anti-inflammatory effects and possible mechanisms of isodojaponin D (19-hydroxy-1alpha,6-diacetoxy-6,7-seco-ent-kaur-16-en-15-one-7,20-olide), a new diterpene isolated from Isodon japonicus against lipopolysaccharide(LPS)-induced microglial activation in BV2 cells. Results from RT-PCR and Western blot showed that pretreatment with isodojaponin D (5 and 10 microg/ml) prior to treatment with LPS (1 microg/ml) significantly decreased LPS-induced production of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in a dose-dependent manner. In addition, LPS-induced pro-inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha, were also decreased by pretreatment with isodojaponin D. This effect was accompanied by a decrease in translocations of Nuclear Factor-KappaB (NF-kappaB) p50 and p65 from the cytoplasm to the nucleus and by a decrease in I kappaB (IkappaB) degradation. In addition, pretreatment with isodojaponin D significantly attenuated LPS-induced mitogen-activated protein kinase (MAPK) activation. Taken together, these results suggest that isodojaponin D suppressed LPS-induced microglial activation and production of pro-inflammatory mediators by inhibition of the NF-kappaB signaling pathway and phosphorylation of MAPKs. These results suggest that isodojaponin D could play a beneficial role in treatment of neurodegenerative disease.
Graduate School of Medicine, Korea University, Seoul 136-701, Republic of Korea.
Ji-Youn
JY
Lim
Tae Joon
TJ
Won
Bang Yeon
BY
Hwang
Hak Rim
HR
Kim
Kwang Woo
KW
Hwang
Donggeun
D
Sul
So-Young
SY
Park
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis
C547088:19-hydroxy-1alpha,6-diacetoxy-6,7-seco-ent-kaur-16-en-15-one-7,20-olide; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004224:Diterpenes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone