title: Schizandrin C exerts anti-neuroinflammatory effects by upregulating phase II detoxifying/antioxidant enzymes in microglia.
abstract: We investigated the anti-neuroinflammatory properties of schizandrin C by focusing on its roles in the induction of phase II detoxifying/antioxidant enzymes and in the modulation of upstream signaling pathways. Schizandrin C induced expression of phase II detoxifying/antioxidant enzymes including heme oxygenase-1 (HO-1) and NADPH dehydrogenase quinone-1 (NQO-1). Activation of upstream signaling pathways, such as the cAMP/protein kinase A/cAMP response element-binding protein (cAMP/PKA/CREB) and erythroid-specific nuclear factor-regulated factor 2 (Nrf-2) pathways, significantly increased following treatment with schizandrin C. In addition, expressions of schizandrin C-mediated phase II detoxifying/antioxidant enzymes were completely attenuated by adenylyl cyclase inhibitor (ddAdo) and protein kinase A (PKA) inhibitor (H-89). In microglia, schizandrin C significantly inhibited lipoteichoic acid (LTA)-stimulated pro-inflammatory cytokines and chemokines, prostaglandin E2 (PGE2), nitric oxide (NO), and reactive oxygen species (ROS) production, and inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and matrix metallopeptidase-9 (MMP-9) protein expressions. Moreover, schizandrin C suppressed LTA-induced nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), janus-kinase/signal transducer and activator of transcription (JAK-STATs), and mitogen-activated protein kinase (MAPK) activation. Schizandrin C also effectively suppressed ROS generation and NO production, as well as iNOS promoter activity in LTA-stimulated microglia. This suppressive effect was reversed by transfection with Nrf-2 and HO-1 siRNA and co-treatment with inhibitors ddAdo and H-89. Our results indicate that schizandrin C isolated from Schisandra chinensis could be used as a natural anti-neuroinflammatory agent, inducing phase II detoxifying/antioxidant enzymes via cAMP/PKA/CREB and Nrf-2 signaling.
authors.affiliation: Pusan National University, Busan, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Tae Gyeong
authors.initials: TG
authors.lastname: Park
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Rajasekar
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Lee
authors.forename: Young-Whan
authors.initials: YW
authors.lastname: Choi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D000975:Antioxidants / Q000378:metabolism; D002461:Cell Line, Transformed; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D034242:Cyclooctanes / Q000008:administration & dosage; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D017705:Lignans / Q000008:administration & dosage*; D008070:Lipopolysaccharides / Q000276:immunology; D050216:Metabolic Detoxication, Phase I / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D009252:NADPH Dehydrogenase / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D008517:Phytotherapy; D011083:Polycyclic Compounds / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D032141:Schisandra / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D013682:Teichoic Acids / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects; D014805:Vitamin B 12 / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D017362:Cyclic AMP Response Element-Binding Protein; D034242:Cyclooctanes; D007546:Isoquinolines; D017705:Lignans; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011083:Polycyclic Compounds; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013449:Sulfonamides; D013682:Teichoic Acids; C096700:2',5'-dideoxyadenosylcobalamin; C009900:lipoteichoic acid; C031409:schizandrin C; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D009252:NADPH Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D014805:Vitamin B 12
keywords: Anti-neuroinflammation; Lipoteichoic acid; Microglia; Phase II detoxifying/antioxidant enzymes; Schizandrin C