Schizandrin C exerts anti-neuroinflammatory effects by upregulating phase II detoxifying/antioxidant enzymes in microglia

Int Immunopharmacol. 2013 Oct;17(2):415-26. doi: 10.1016/j.intimp.2013.06.032. Epub 2013 Jul 13.


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.

Keywords: Anti-neuroinflammation; Lipoteichoic acid; Microglia; Phase II detoxifying/antioxidant enzymes; Schizandrin C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage*
  • Antioxidants / metabolism
  • Cell Line, Transformed
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclooctanes / administration & dosage
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Isoquinolines / pharmacology
  • Lignans / administration & dosage*
  • Lipopolysaccharides / immunology
  • Metabolic Detoxication, Phase I / physiology
  • Mice
  • Microglia / drug effects*
  • Microglia / immunology
  • NADPH Dehydrogenase / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Phytotherapy*
  • Polycyclic Compounds / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Small Interfering / genetics
  • Schisandra / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sulfonamides / pharmacology
  • Teichoic Acids / immunology
  • Transcriptional Activation / drug effects
  • Vitamin B 12 / analogs & derivatives
  • Vitamin B 12 / pharmacology


  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Cyclic AMP Response Element-Binding Protein
  • Cyclooctanes
  • Isoquinolines
  • Lignans
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Polycyclic Compounds
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Sulfonamides
  • Teichoic Acids
  • 2',5'-dideoxyadenosylcobalamin
  • lipoteichoic acid
  • schizandrin C
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • NADPH Dehydrogenase
  • Cyclic AMP-Dependent Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Vitamin B 12