Anti-inflammatory effects of saponins derived from the roots of Platycodon grandiflorus in lipopolysaccharide‑stimulated BV2 microglial cells.

Radix platycodi is the root of Platycodon grandiflorus A. DC, which has been widely used as a food material and for the treatment of a number of chronic inflammatory diseases in traditional oriental medicine. In this study, the anti‑inflammatory effects of the saponins isolated from radix platycodi (PGS) on the production of inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated BV2 murine microglial cells were examined. We also investigated the effects of PGS on LPS‑induced nuclear factor‑κB (NF-κB) activation and phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways. Following stimulation with LPS, elevated nitric oxide (NO), prostaglandin E2 (PGE2) and pro-inflammatory cytokine production was detected in the BV2 microglial cells. However, PGS significantly inhibited the excessive production of NO, PGE2 and pro‑inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner without causing any cytotoxic effects. In addition, PGS suppressed NF-κB translocation and inhibited the LPS-induced phosphorylation of AKT and MAPKs. Our results indicate that the inhibitory effect of PGS on LPS-stimulated inflammatory response in BV2 microglial cells is associated with the suppression of NF-κB activation and the PI3K/AKT and MAPK signaling pathways. Therefore, these findings suggest that PGS may be useful in the treatment of neurodegenerative diseases by inhibiting inflammatory responses in activated microglial cells.

[1]  Kyooseob Ha,et al.  A new synthetic chalcone derivative, 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139), suppresses the Toll-like receptor 4-mediated inflammatory response through inhibition of the Akt/NF-κB pathway in BV2 microglial cells , 2012, Experimental & Molecular Medicine.

[2]  C. Pan,et al.  Protopine reduces the inflammatory activity of lipopolysaccharide-stimulated murine macrophages. , 2012, BMB reports.

[3]  R. Tostes,et al.  Differential Modulation of Nitric Oxide Synthases in Aging: Therapeutic Opportunities , 2012, Front. Physio..

[4]  E. Ling,et al.  Role of microglia in the process of inflammation in the hypoxic developing brain. , 2011, Frontiers in bioscience.

[5]  D. Loane,et al.  Role of microglia in neurotrauma , 2010, Neurotherapeutics.

[6]  Jia Wei,et al.  Signaling pathways associated with inflammatory bowel disease. , 2010, Recent patents on inflammation & allergy drug discovery.

[7]  J. Scher,et al.  The Anti-Inflammatory Effects of Prostaglandins , 2009, Journal of Investigative Medicine.

[8]  R. McManus,et al.  NF-κB regulation: the nuclear response , 2009, Journal of cellular and molecular medicine.

[9]  H. Neumann,et al.  Microglial clearance function in health and disease , 2009, Neuroscience.

[10]  E. Ling,et al.  Antioxidants and neuroprotection in the adult and developing central nervous system. , 2008, Current medicinal chemistry.

[11]  Eun Bang Lee,et al.  Anti-inflammatory activity of prosapogenin methyl ester of platycodin D via nuclear factor-kappaB pathway inhibition. , 2008, Biological & pharmaceutical bulletin.

[12]  L. McCullough,et al.  Function of COX-2 and Prostaglandins in Neurological Disease , 2007, Journal of Molecular Neuroscience.

[13]  Yung-Hyun Choi,et al.  Anti-inflammatory effects of beta-lapachone in lipopolysaccharide-stimulated BV2 microglia. , 2007, International immunopharmacology.

[14]  Jae Woong Lee,et al.  Inhibitory Effect of Inflexinol on Nitric Oxide Generation and iNOS Expression via Inhibition of NF-κB Activation , 2007, Mediators of inflammation.

[15]  A. Suzumura,et al.  Roles of Glia‐Derived Cytokines on Neuronal Degeneration and Regeneration , 2006, Annals of the New York Academy of Sciences.

[16]  Jeongseon Kim,et al.  Effects of Platycodon grandiflorum on lipopolysaccharide-stimulated production of prostaglandin E2, nitric oxide, and interleukin-8 in mouse microglial BV2 cells. , 2006, Journal of medicinal food.

[17]  J. Ashwell The many paths to p38 mitogen-activated protein kinase activation in the immune system , 2006, Nature Reviews Immunology.

[18]  D. Dou,et al.  Five new triterpenoid saponins from the roots of Platycodon grandiflorum. , 2006, Chemical & pharmaceutical bulletin.

[19]  I. Kang,et al.  Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-α production through inhibition of PI 3-kinase/Akt and NF-κB activation in murine BV2 microglial cells , 2006, Neuroscience Letters.

[20]  P. Peterson,et al.  Microglia as a Pharmacological Target in Infectious and Inflammatory Diseases of the Brain , 2006, Journal of Neuroimmune Pharmacology.

[21]  A. Signore,et al.  Inflammatory bowel diseases: clinical update of practical guidelines , 2005, Nuclear medicine communications.

[22]  K. Ahn,et al.  Inhibition of inducible nitric oxide synthase and cyclooxygenase II by Platycodon grandiflorum saponins via suppression of nuclear factor-kappaB activation in RAW 264.7 cells. , 2005, Life sciences.

[23]  Song-Kyu Park,et al.  Activation of mitogen-activated protein kinases and AP-1 by polysaccharide isolated from the radix of Platycodon grandiflorum in RAW 264.7 cells. , 2004, International immunopharmacology.

[24]  Eun Bang Lee,et al.  Platycodin D and D3 isolated from the root of Platycodon grandiflorum modulate the production of nitric oxide and secretion of TNF-alpha in activated RAW 264.7 cells. , 2004, International immunopharmacology.

[25]  Ji-Young Lee,et al.  Antioxidant and anticancer activities of organic extracts from Platycodon grandiflorum A. De Candolle roots. , 2004, Journal of ethnopharmacology.

[26]  P. Eikelenboom,et al.  Neuroinflammatory perspectives on the two faces of Alzheimer’s disease , 2004, Journal of Neural Transmission.

[27]  M. Hüll,et al.  Synergistic inhibitory effect of ascorbic acid and acetylsalicylic acid on prostaglandin E2 release in primary rat microglia , 2003, Journal of neurochemistry.

[28]  M. Giovannini,et al.  Experimental brain inflammation and neurodegeneration as model of Alzheimer's disease: protective effects of selective COX-2 inhibitors. , 2003, International journal of immunopathology and pharmacology.

[29]  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.

[30]  G. Johnson,et al.  Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases , 2002, Science.

[31]  T. Owens Identification of new therapeutic targets for prevention of CNS inflammation , 2002, Expert opinion on therapeutic targets.

[32]  E. Nardin The role of inflammatory and immunological mediators in periodontitis and cardiovascular disease. , 2001 .

[33]  S. Y. Kim,et al.  Inhibition of prostaglandin E2 production by platycodin D isolated from the root of Platycodon grandiflorum. , 2001, Planta medica.

[34]  S. Kassis,et al.  Inhibition of p38 mitogen‐activated protein kinase provides neuroprotection in cerebral focal ischemia , 2001, Medicinal research reviews.

[35]  M. Mayo,et al.  Akt Suppresses Apoptosis by Stimulating the Transactivation Potential of the RelA/p65 Subunit of NF-κB , 2000, Molecular and Cellular Biology.

[36]  G. Feuerstein,et al.  Inflammation and Stroke: Putative Role for Cytokines, Adhesion Molecules and iNOS in Brain Response to Ischemia , 2000, Brain pathology.

[37]  P. Wang,et al.  Current trends in the development of nitric oxide donors. , 1999, Current pharmaceutical design.

[38]  E. Hirsch,et al.  FcεRII/CD23 Is Expressed in Parkinson’s Disease and Induces, In Vitro, Production of Nitric Oxide and Tumor Necrosis Factor-α in Glial Cells , 1999, The Journal of Neuroscience.

[39]  G L Johnson,et al.  Organization and regulation of mitogen-activated protein kinase signaling pathways. , 1999, Current opinion in cell biology.

[40]  G. Levi,et al.  Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. , 1998, Biochimie.

[41]  S. Siciliano,et al.  Diversity of root-associated bacteria associated with field-grown canola (Brassica napus L.) and wheat (Triticum aestivum L.) , 1998 .

[42]  M. Ross,et al.  Molecular Pathology of Cerebral Ischemia: Delayed Gene Expression and Strategies for Neuroprotection a , 1997, Annals of the New York Academy of Sciences.

[43]  J. Abrams,et al.  Beneficial actions of nitrates in cardiovascular disease. , 1996, The American journal of cardiology.

[44]  J. Mitchell,et al.  Cyclooxygenase-2: regulation and relevance in inflammation. , 1995, Biochemical pharmacology.

[45]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[46]  E. Hirsch,et al.  Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease , 1994, Neuroscience Letters.

[47]  S Moncada,et al.  Nitric oxide synthases in mammals. , 1994, The Biochemical journal.

[48]  T. Marunouchi,et al.  Production of tumor necrosis factor-alpha by microglia and astrocytes in culture , 1989, Brain Research.

[49]  V. Perry,et al.  Macrophages and microglia in the nervous system , 1988, Trends in Neurosciences.

[50]  H. Ishii,et al.  Structures of polygalacin-D and -D2, platycodin-D and -D2, and their monoacetates, saponins isolated from Platycodon grandiflorum A. DC., determined by carbon-13 nuclear magnetic resonance spectroscopy. , 1978 .

[51]  N. Rothwell,et al.  Perspectives Series: Cytokines and The Brain The Role of Interleukin 1 in Acute Neurodegeneration and Stroke: Pathophysiological and Therapeutic Implications , 2013 .

[52]  A. Redington,et al.  Nitric Oxide Synthase Inhibition , 2004, Treatments in respiratory medicine.

[53]  M. O’Banion,et al.  Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology. , 1999, Critical reviews in neurobiology.

[54]  C. Nathan,et al.  Nitric oxide and macrophage function. , 1997, Annual review of immunology.