Sesquiterpene dimer (DSF-52) from Artemisia argyi inhibits microglia-mediated neuroinflammation via suppression of NF-κB, JNK/p38 MAPKs and Jak2/Stat3 signaling pathways.
Microglia-involved neuroinflammation is thought to promote brain damage in various neurodegenerative disorders. Therefore, novel therapeutics suppressing microglia over-activation could prove useful for neuroprotection in inflammation-mediated neurodegenerative diseases. DSF-52 is a novel sesquiterpene dimer compound isolated from medical plant Artemisia argyi by our group. In this study, we investigated whether DSF-52 inhibited the neuroinflammatory responses in lipopolysaccharide (LPS)-activated microglia. Our findings showed that DSF-52 inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), as well as mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin-1β (IL-1β), granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage inflammatory protein-1α (MIP-1α) in LPS-activated BV-2 microglia. Moreover, DSF-52 markedly up-regulated mRNA levels of anti-inflammatory cytokine IL-10. Mechanism study indicated that DSF-52 suppressed Akt/IκB/NF-κB inflammation pathway against LPS treatment. Also, DSF-52 down-regulated the phosphorylation levels of JNK and p38 MAPKs, but not ERK. Furthermore, DSF-52 blocked Jak2/Stat3 dependent inflammation pathway through inhibiting Jak2 and Stat3 phosphorylation, as well as Stat3 nuclear translocation. We concluded that the inhibitory ability of DSF-52 on microglia-mediated neuroinflammation may offer a novel neuroprotective modality and could be potentially useful in inflammation-mediated neurodegenerative diseases.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Ke-Wu
KW
Zeng
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Medicinal Chemistry and Pharmaceutical Analysis, Logistics College of Chinese People's Armed Police Forces, Tianjin 300162, China.
Shu
S
Wang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Xin
X
Dong
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Yong
Y
Jiang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: pengfeitu@vip.163.com.
Peng-Fei
PF
Tu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D019306:Artemisia / Q000737:chemistry*; D001692:Biological Transport; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D054830:Sesterterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; C000593039:DSF-52; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010936:Plant Extracts; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D054830:Sesterterpenes; D014157:Transcription Factors; D011494:Protein Kinases; D053614:Janus Kinase 2; D048051:p38 Mitogen-Activated Protein Kinases
Microglia; Neuroinflammation; Sesquiterpene dimer; Signaling pathway