Anti-neuroinflammatory activity of nobiletin on suppression of microglial activation.
A growing body of evidence suggests that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) from the peel of citrus fruits, enhances the damaged cognitive function in disease animal models. However, the neuroprotective mechanism has not been clearly elucidated. Since nobiletin has shown anti-inflammatory effects in several tissues, we investigated whether nobiletin suppresses excessive microglial activation implicated in neurotoxicity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cell culture models. Release of nitric oxide (NO), the major inflammatory mediator in microglia, was markedly suppressed in a dose-dependent manner following nobiletin treatment (1-50 µM) in LPS-stimulated BV-2 microglia cells. The inhibitory effect of nobiletin was similar to that of minocycline, a well-known microglial inactivator. Nobiletin significantly inhibited the release of the pro-inflammatory cytokine tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β). LPS-induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were also significantly inhibited by nobiletin treatment. In addition, nobiletin markedly inhibited the LPS-induced pro-inflammatory transcription factor nuclear factor κB (NF-κB) signaling pathway by suppressing nuclear NF-κB translocation from the cytoplasm and subsequent expression of NF-κB in the nucleus. Taken together, these results may contribute to further exploration of the therapeutic potential and molecular mechanism of nobiletin in relation to neuroinflammation and neurodegenerative diseases.
Institute of Medical Science, Jeju National University School of Medicine, 66 Jejudaehakno, Jeju-si, Jeju-do 690–756, Republic of Korea.
Yanji
Y
Cui
Jinji
J
Wu
Sung-Cherl
SC
Jung
Deok-Bae
DB
Park
Young-Hee
YH
Maeng
Jeong Yun
JY
Hong
Se-Jae
SJ
Kim
Sun-Ryung
SR
Lee
Soon-Jong
SJ
Kim
Sang Jeong
SJ
Kim
Su-Yong
SY
Eun
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002957:Citrus / Q000737:chemistry*; D016207:Cytokines / Q000037:antagonists & inhibitors; D003593:Cytoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005638:Fruit; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010936:Plant Extracts; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D008911:Minocycline