Schizandrin C exerts anti-neuroinflammatory effects by upregulating phase II detoxifying/antioxidant enzymes in microglia.
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.
['Park|Sun Young|SY|', 'Park|Se Jin|SJ|', 'Park|Tae Gyeong|TG|', 'Rajasekar|Seetharaman|S|', 'Lee|Sang-Joon|SJ|', 'Choi|Young-Whan|YW|']
D000818:Animals D000894:Anti-Inflammatory Agents, Non-Steroidal D000975:Antioxidants D002461:Cell Line, Transformed D017362:Cyclic AMP Response Element-Binding Protein D017868:Cyclic AMP-Dependent Protein Kinases D034242:Cyclooctanes D004789:Enzyme Activation D051547:Heme Oxygenase-1 D007546:Isoquinolines D017705:Lignans D008070:Lipopolysaccharides D050216:Metabolic Detoxication, Phase I D051379:Mice D017628:Microglia D009252:NADPH Dehydrogenase D051267:NF-E2-Related Factor 2 D008517:Phytotherapy D011083:Polycyclic Compounds D047428:Protein Kinase Inhibitors D034741:RNA, Small Interfering D032141:Schisandra D015398:Signal Transduction D013449:Sulfonamides D013682:Teichoic Acids D015533:Transcriptional Activation D014805:Vitamin B 12
Schizandrin C Phase II detoxifying/antioxidant enzymes Microglia Lipoteichoic acid Anti-neuroinflammation