Abstract
Microglia-involved neuroinflammation is thought to promote brain damage in various neurodegenerative disorders. Thus, inhibition of microglial over-activation may have a therapeutic benefit for the treatment of neurodegenerative disorders. Micheliolide (MCL) is a sesquiterpene lactone which inhibits various inflammatory response. However, whether MCL can inhibit neuroinflammation caused by LPS-activated BV2 microglia has not yet been explored. In this study, we demonstrated that treatment of BV2 cells with MCL significantly repressed LPS-stimulated nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, as well as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) induction. MCL also attenuated mRNA levels of multiple pro-inflammatory cytokines and mediators such as iNOS, COX-2, TNF-α, IL-6 and IL-1β. Mechanistic studies revealed that MCL suppressed LPS-stimulated the activation of IκBα/NF-κB pathway and Akt pathway. Moreover, MCL inhibited LPS-induced the activition of c-Jun N-terminal kinase (JNK), p38 MAPK kinase, and extracellular signal-regulated kinases 1/2 (ERK1/2). Meanwhile, MCL markedly promoted antioxidant protein heme oxygenase-1 (HO-1) expression by enhancing NF-E2-related factor 2 (Nrf2) activity. Together, our results imply that MCL may serve as a neuroprotective agent in neuroinflammation-related neurodegenerative disorders.
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Cell Line, Transformed
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Gene Expression Regulation / drug effects*
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism
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Humans
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Lipopolysaccharides / antagonists & inhibitors*
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Microglia / cytology
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Microglia / drug effects*
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Microglia / metabolism
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neuroprotective Agents / pharmacology*
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Sesquiterpenes, Guaiane / pharmacology*
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Signal Transduction
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents
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IL1B protein, mouse
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Interleukin-1beta
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Interleukin-6
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Lipopolysaccharides
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Membrane Proteins
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NF-E2-Related Factor 2
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NF-kappa B
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Neuroprotective Agents
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Nfe2l2 protein, mouse
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Sesquiterpenes, Guaiane
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Tumor Necrosis Factor-alpha
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interleukin-6, mouse
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micheliolide
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Heme Oxygenase-1
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Hmox1 protein, mouse
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Proto-Oncogene Proteins c-akt
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
Grants and funding
This work was supported by Ministry of Science and Technology of the People's Republic of China (MOST) Grants 2013CB530801 and 2014CB910503, and National Natural Science Foundation of China (NSFC) Grant 81370455. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.