Anti-inflammatory effects of glaucocalyxin B in microglia cells.

Over-activated microglia is involved in various kinds of neurodegenerative process including Parkinson, Alzheimer and HIV dementia. Suppression of microglial over activation has emerged as a novel strategy for treatment of neuroinflammation-based neurodegeneration. In the current study, anti-inflammatory and neuroprotective effects of the ent-kauranoid diterpenoids, which were isolated from the aerial parts of Rabdosia japonica (Burm. f.) var. glaucocalyx (Maxim.) Hara, were investigated in cultured microglia cells. Glaucocalyxin B (GLB), one of five ent-kauranoid diterpenoids, significantly decreased the generation of nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in the lipopolysaccharide (LPS)-activated microglia cells. In addition, GLB inhibited activation of nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS) in LPS-activated microglia cells. Furthermore, GLB strongly induced the expression of heme oxygenase (HO)-1 in BV-2 microglia cells. Finally, GLB exhibited neuroprotective effect by preventing over-activated microglia induced neurotoxicity in a microglia/neuron co-culture model. Taken together, the present study demonstrated that the GLB possesses anti-nueroinflammatory activity, and might serve as a potential therapeutic agent for treating neuroinflammatory diseases.

[1]  C. Glass,et al.  Microglial cell origin and phenotypes in health and disease , 2011, Nature Reviews Immunology.

[2]  S. Yim,et al.  Curcumin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator protein 1 and nuclear factor kappab bindings in BV2 microglial cells. , 2004, Journal of pharmacological sciences.

[3]  V. Perry,et al.  Microglial priming in neurodegenerative disease , 2014, Nature Reviews Neurology.

[4]  Bin Liu,et al.  Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic Intervention , 2003, Journal of Pharmacology and Experimental Therapeutics.

[5]  B. Hwang,et al.  Methylalpinumisoflavone Inhibits Lipopolysaccharide‐Induced Inflammation in Microglial Cells by the NF‐kappaB and MAPK Signaling Pathway , 2012, Phytotherapy research : PTR.

[6]  J. Koistinaho,et al.  Role of p38 and p44/42 mitogen‐activated protein kinases in microglia , 2002, Glia.

[7]  Sunyoung Park,et al.  Pheophytin a and chlorophyll a suppress neuroinflammatory responses in lipopolysaccharide and interferon-γ-stimulated BV2 microglia. , 2014, Life sciences.

[8]  Fali Zhang,et al.  1-O-tigloyl-1-O-deacetyl-nimbolinin B inhibits LPS-stimulated inflammatory responses by suppressing NF-κB and JNK activation in microglia cells. , 2014, Journal of pharmacological sciences.

[9]  John C. Lee,et al.  Extracellular Signal-Regulated Kinase and p38 Subgroups of Mitogen-Activated Protein Kinases Regulate Inducible Nitric Oxide Synthase and Tumor Necrosis Factor-α Gene Expression in Endotoxin-Stimulated Primary Glial Cultures , 1998, The Journal of Neuroscience.

[10]  E. Abraham,et al.  Involvement of Reactive Oxygen Species in Toll-Like Receptor 4-Dependent Activation of NF-κB 1 , 2004, The Journal of Immunology.

[11]  Zheng-Tao Wang,et al.  [Effect of glaucocalyxin A on level of Th1/Th2 type cytokines in mice]. , 2006, Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica.

[12]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[13]  J. Hyun,et al.  Anti‐inflammatory mechanism of ginsenoside Rh1 in lipopolysaccharide‐stimulated microglia: critical role of the protein kinase A pathway and hemeoxygenase‐1 expression , 2010, Journal of neurochemistry.

[14]  S. Koppula,et al.  MMHD [(S,E)-2-methyl-1-(2-methylthiazol-4-yl) hexa-1,5-dien-ol], a novel synthetic compound derived from epothilone, suppresses nuclear factor-kappaB-mediated cytokine expression in lipopolysaccharide-stimulated BV-2 microglia. , 2010, Journal of pharmacological sciences.

[15]  Han-Dong Sun,et al.  Diterpenoids from Isodon species and their biological activities. , 2006, Natural product reports.

[16]  Bo Gao,et al.  Antiinflammatory effects of orientin-2"-O-galactopyranoside on lipopolysaccharide-stimulated microglia. , 2014, Biological & pharmaceutical bulletin.

[17]  K. Suk,et al.  Anti-inflammatory effects of a fluorovinyloxyacetamide compound KT-15087 in microglia cells. , 2009, Pharmacological research.

[18]  Y. Tsai,et al.  Ligustilide prevents LPS-induced iNOS expression in RAW 264.7 macrophages by preventing ROS production and down-regulating the MAPK, NF-κB and AP-1 signaling pathways. , 2011, International immunopharmacology.

[19]  Hee-Sun Kim,et al.  Lancemaside A inhibits microglial activation via modulation of JNK signaling pathway. , 2013, Biochemical and biophysical research communications.

[20]  Bin Wang,et al.  Glaucocalyxin A induces apoptosis in human leukemia HL-60 cells through mitochondria-mediated death pathway. , 2011, Toxicology in vitro : an international journal published in association with BIBRA.

[21]  Jian Cheng,et al.  Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke , 2014, Brain, Behavior, and Immunity.

[22]  S. Koppula,et al.  Regulation of Microglia Activity by Glaucocalyxin-A: Attenuation of Lipopolysaccharide-Stimulated Neuroinflammation through NF-κB and p38 MAPK Signaling Pathways , 2013, PloS one.

[23]  N. Mackman,et al.  LPS induction of gene expression in human monocytes. , 2001, Cellular signalling.

[24]  K. Takata,et al.  Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: tangle formation, amyloid-β, and microglia in Alzheimer's disease. , 2012, Journal of pharmacological sciences.

[25]  Chemical genetics of neuroinflammation: natural and synthetic compounds as microglial inhibitors , 2012, Inflammopharmacology.

[26]  T. Cindrova-Davies.  Gabor Than Award Lecture 2008: pre-eclampsia - from placental oxidative stress to maternal endothelial dysfunction. , 2009, Placenta.

[27]  Xuechu Zhen,et al.  Design, synthesis and evaluation of a series of non-steroidal anti-inflammatory drug conjugates as novel neuroinflammatory inhibitors. , 2015, International immunopharmacology.

[28]  F. Fan,et al.  Redox regulation of glial inflammatory response to lipopolysaccharide and interferonγ , 2004, Journal of neuroscience research.

[29]  Hye-Eun Kim,et al.  Caffeoylserotonin Protects Human Keratinocyte HaCaT Cells against H2O2‐Induced Oxidative Stress and Apoptosis through Upregulation of HO‐1 Expression via Activation of the PI3K/Akt/Nrf2 Pathway , 2013, Phytotherapy research : PTR.

[30]  Ik-Soo Lee,et al.  Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells , 2011, Neurochemistry International.

[31]  M. Block,et al.  Microglia-mediated neurotoxicity: uncovering the molecular mechanisms , 2007, Nature Reviews Neuroscience.

[32]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[33]  Jin Yr,et al.  Studies on chemical constituents in the roots of Rabdosia japonica (Burm.f). Hara var. glaucocalyx (Maxin) Hara , 2000 .

[34]  P. Mcgeer,et al.  The Role of Anti-Inflammatory Agents in Parkinson’s Disease , 2007, CNS drugs.

[35]  P. Tak,et al.  NF-κB: a key role in inflammatory diseases , 2001 .

[36]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[37]  K. Suk,et al.  Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. , 2008, International immunopharmacology.

[38]  J. Serratosa,et al.  High‐yield isolation of murine microglia by mild trypsinization , 2003, Glia.

[39]  D. Park,et al.  S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-κB activation in gastric cancer cells , 2013, Molecules and cells.

[40]  H. Liou,et al.  Regulation of the Immune System by NF-κB and IκB , 2002 .

[41]  G. P. Dubey,et al.  Neuroprotective Effect of Curcuminoids Against Inflammation-Mediated Dopaminergic Neurodegeneration in the MPTP Model of Parkinson’s Disease , 2012, Journal of Neuroimmune Pharmacology.

[42]  Fred H. Gage,et al.  Mechanisms Underlying Inflammation in Neurodegeneration , 2010, Cell.

[43]  M. Gorospe,et al.  Mitogen-activated protein kinase (MAPK) activation by butylated hydroxytoluene hydroperoxide: implications for cellular survival and tumor promotion. , 1996, Cancer research.

[44]  Bin Liu,et al.  Critical Role for Microglial NADPH Oxidase in Rotenone-Induced Degeneration of Dopaminergic Neurons , 2003, The Journal of Neuroscience.

[45]  D. Walker,et al.  Microglia in degenerative neurological disease , 1993, Glia.

[46]  S. Aid,et al.  Inhibition of NADPH oxidase promotes alternative and anti‐inflammatory microglial activation during neuroinflammation , 2012, Journal of neurochemistry.

[47]  Jingying Zhu,et al.  Involvement of mitogen‐activated protein kinase and NF‐κB signaling pathways in perfluorooctane sulfonic acid‐induced inflammatory reaction in BV2 microglial cells , 2015, Journal of applied toxicology : JAT.

[48]  Y. Naito,et al.  Heme oxygenase-1 and anti-inflammatory M2 macrophages. , 2014, Archives of biochemistry and biophysics.

[49]  I. Verma,et al.  NF-κB regulation in the immune system , 2002, Nature Reviews Immunology.

[50]  S. Koppula,et al.  Anti-neuroinflammatory activity of a novel cannabinoid derivative by inhibiting the NF-κB signaling pathway in lipopolysaccharide-induced BV-2 microglial cells. , 2013, Journal of pharmacological sciences.

[51]  Z. Bin,et al.  Inhibition by Glaucocalyxin A of Aggregation of Rabbit Platelets Induced by ADP, Arachidonic Acid and Platelet-Activating Factor, and Inhibition of [3H]-PAF Binding , 1992, Thrombosis and Haemostasis.

[52]  W. Lesslauer,et al.  Blockade of p38 Mitogen-activated Protein Kinase Pathway Inhibits Inducible Nitric-oxide Synthase Expression in Mouse Astrocytes* , 1997, The Journal of Biological Chemistry.

[53]  L. Hsiao,et al.  Cigarette smoke extract upregulates heme oxygenase-1 via PKC/NADPH oxidase/ROS/PDGFR/PI3K/Akt pathway in mouse brain endothelial cells , 2011, Journal of Neuroinflammation.

[54]  P. Mcgeer,et al.  Inflammation and neurodegeneration in Parkinson's disease. , 2004, Parkinsonism & related disorders.

[55]  S. Koppula,et al.  Anti-neuroinflammatory activity of Kamebakaurin from Isodon japonicus via inhibition of c-Jun NH₂-terminal kinase and p38 mitogen-activated protein kinase pathway in activated microglial cells. , 2011, Journal of pharmacological sciences.

[56]  G. Levi,et al.  Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide , 1998, Progress in Neurobiology.

[57]  G. Baltuch,et al.  Microglia as mediators of inflammatory and degenerative diseases. , 1999, Annual review of neuroscience.

[58]  K. Miyao,et al.  Tumor Necrosis Factor-α Mediates the Blood–Brain Barrier Dysfunction Induced by Activated Microglia in Mouse Brain Microvascular Endothelial Cells , 2010 .