Skip to main content

Advertisement

SpringerLink
Log in

A Novel Synthetic Compound 4-Acetyl-3-methyl-6-(2-bromophenyl)pyrano[3,4-c]pyran-1,8-dione Inhibits the Production of Nitric Oxide and Proinflammatory Cytokines Via the NF-κB Pathway in Lipopolysaccharide-Activated Microglia Cells

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Previously, we discovered a new compound, 1H,8H-Pyrano[3,4-c]pyran-1,8-dione (PPY), from Vitex rotundifolia L. and evaluated its anti-inflammatory and anti-asthmatic effects. In this study, we synthesized a new, modified compound 4-acetyl-3-methyl-6-(2-bromophenyl)pyrano[3,4-c]pyran-1,8-dione (PPY-Br) based on the PPY skeleton and evaluated its anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglia. PPY-Br suppresses nitric oxide production, inducible nitric oxide synthase expression, and tumor necrosis factor-α and interleukin-6 production in LPS-activated BV-2 microglial cell line and mouse primary microglia. The effect of PPY-Br on the activation of nuclear factor (NF)-kappaB was examined to identify the mechanism involved. The LPS-induced translocation of NF-κB to the nucleus and phosphorylation of inhibitory-kappaB were almost completely blocked by PPY-Br. This study indicates that PPY-Br significantly attenuates the level of neurotoxic, proinflammatory mediators and proinflammatory cytokines via inhibition of the NF-κB signaling pathway. We suggest that PPY-Br presents a new candidate treatment for various neuro-inflammatory diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yang I, Han SJ, Kaur G, Crane C, Parsa AT (2010) The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17:6–10

    Article  PubMed  Google Scholar 

  2. Wyss-Coray T, Mucke L (2002) Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35:419–432

    Article  PubMed  CAS  Google Scholar 

  3. Nathan CF, Hibbs JB Jr (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 3:65–70

    Article  PubMed  CAS  Google Scholar 

  4. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL et al (2000) Inflammation and alzheimer’s disease. Neurobiol Aging 21:383–421

    Article  PubMed  CAS  Google Scholar 

  5. McGeer PL, McGeer EG (2004) Inflammation and neurodegeneration in parkinson’s disease. Parkinsonism Relat Disord 10(Suppl 1):S3–S7

    Article  PubMed  Google Scholar 

  6. Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62:127–136

    PubMed  CAS  Google Scholar 

  7. Chao CC, Hu S, Peterson PK (1995) Glia, cytokines, and neurotoxicity. Crit Rev Neurobiol 9:189–205

    PubMed  CAS  Google Scholar 

  8. Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987) Anti-cachectin/tnf monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–664

    Article  PubMed  CAS  Google Scholar 

  9. Baker SJ, Reddy EP (1998) Modulation of life and death by the tnf receptor superfamily. Oncogene 17:3261–3270

    Article  PubMed  Google Scholar 

  10. Vilcek J, Lee TH (1991) Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem 266:7313–7316

    PubMed  CAS  Google Scholar 

  11. Sweet MJ, Hume DA (1996) Endotoxin signal transduction in macrophages. J Leukoc Biol 60:8–26

    PubMed  CAS  Google Scholar 

  12. Kuprash DV, Udalova IA, Turetskaya RL, Rice NR, Nedospasov SA (1995) Conserved kappa b element located downstream of the tumor necrosis factor alpha gene: distinct nf-kappa b binding pattern and enhancer activity in lps activated murine macrophages. Oncogene 11:97–106

    PubMed  CAS  Google Scholar 

  13. Lee H, Han AR, Kim Y, Choi SH, Ko E, Lee NY, Jeong JH, Kim SH, Bae H (2009) A new compound, 1h,8h-pyrano[3,4-c]pyran-1,8-dione, suppresses airway epithelial cell inflammatory responses in a murine model of asthma. Int J Immunopathol Pharmacol 22:591–603

    PubMed  CAS  Google Scholar 

  14. Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237

    Article  PubMed  CAS  Google Scholar 

  15. Saura J, Tusell JM, Serratosa J (2003) High-yield isolation of murine microglia by mild trypsinization. Glia 44:183–189

    Article  PubMed  Google Scholar 

  16. Cory AH, Owen TC, Barltrop JA, Cory JG (1991) Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture. Cancer Commun 3:207–212

    PubMed  CAS  Google Scholar 

  17. Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C (1992) Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256:225–228

    Article  PubMed  CAS  Google Scholar 

  18. Bal-Price A, Brown GC (2001) Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity. J Neurosci 21:6480–6491

    PubMed  CAS  Google Scholar 

  19. Woo MS, Jung SH, Hyun JW, Kim HS (2004) Differential regulation of inducible nitric oxide synthase and cytokine gene expression by forskolin and dibutyryl-camp in lipopolysaccharide-stimulated murine bv2 microglial cells. Neurosci Lett 356:187–190

    Article  PubMed  CAS  Google Scholar 

  20. Fiebich BL, Schleicher S, Butcher RD, Craig A, Lieb K (2000) The neuropeptide substance p activates p38 mitogen-activated protein kinase resulting in il-6 expression independently from nf-kappa b. J Immunol 165:5606–5611

    PubMed  CAS  Google Scholar 

  21. Rao A (1994) Nf-atp: a transcription factor required for the co-ordinate induction of several cytokine genes. Immunol Today 15:274–281

    Article  PubMed  CAS  Google Scholar 

  22. Stoll G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the cns. Prog Neurobiol 58:233–247

    Article  PubMed  CAS  Google Scholar 

  23. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the cns. Trends Neurosci 19:312–318

    Article  PubMed  CAS  Google Scholar 

  24. Vila M, Jackson-Lewis V, Guegan C, Wu DC, Teismann P, Choi DK, Tieu K, Przedborski S (2001) The role of glial cells in parkinson’s disease. Curr Opin Neurol 14:483–489

    Article  PubMed  CAS  Google Scholar 

  25. Sriram K, Matheson JM, Benkovic SA, Miller DB, Luster MI, O’Callaghan JP (2006) Deficiency of tnf receptors suppresses microglial activation and alters the susceptibility of brain regions to mptp-induced neurotoxicity: role of tnf-alpha. Faseb J 20:670–682

    Article  PubMed  CAS  Google Scholar 

  26. Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA (2001) Possible new role for nf-kappab in the resolution of inflammation. Nat Med 7:1291–1297

    Article  PubMed  CAS  Google Scholar 

  27. Makarov SS (2001) Nf-kappa b in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Res 3:200–206

    Article  PubMed  CAS  Google Scholar 

  28. Boje KM, Arora PK (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587:250–256

    Article  PubMed  CAS  Google Scholar 

  29. Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM (1998) P48/stat-1alpha-containing complexes play a predominant role in induction of ifn-gamma-inducible protein, 10 kDa (ip-10) by ifn-gamma alone or in synergy with tnf-alpha. J Immunol 161:4736–4744

    PubMed  CAS  Google Scholar 

  30. Piao HZ, Choi IY, Park JS, Kim HS, Cheong JH, Son KH, Jeon SJ, Ko KH, Kim WK (2008) Wogonin inhibits microglial cell migration via suppression of nuclear factor-kappa b activity. Int Immunopharmacol 8:1658–1662

    Article  PubMed  CAS  Google Scholar 

  31. Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW (2006) Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 26:10709–10716

    Article  PubMed  CAS  Google Scholar 

  32. Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P (2010) Massive gliosis induced by interleukin-6 suppresses a beta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J 24:548–559

    Article  PubMed  CAS  Google Scholar 

  33. Chakrabarty P, Herring A, Ceballos-Diaz C, Das P, Golde TE (2011) Hippocampal expression of murine tnfalpha results in attenuation of amyloid deposition in vivo. Mol Neurodegener 6:16

    Article  PubMed  CAS  Google Scholar 

  34. Weitz TM, Town T (2012) Microglia in alzheimer’s disease: it’s all about context. Int J Alzheimers Dis 2012:314185

    PubMed  Google Scholar 

  35. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, Ruano D, Vizuete M, Gutierrez A, Vitorica J (2008) Inflammatory response in the hippocampus of ps1m146 l/app 751sl mouse model of alzheimer’s disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 28:11650–11661

    Article  PubMed  CAS  Google Scholar 

  36. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374:647–650

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government [MEST] (No. 2012-0005755) and by a grant from the Kyung Hee University in 2007. (KHU-20070627).

Author information

Authors and Affiliations

  1. Department of Physiology, College of Oriental Medicine, Kyung Hee University, #1 Hoeki-Dong, Dongdaemoon-gu, Seoul, 130-701, Republic of Korea

    Hwan-Suck Chung, Sae-Noon Kim & Hyunsu Bae

  2. College of Pharmacy, Yonsei University, 162-1 Songdo-dong, Yonsooku, Inchon, 406-840, Republic of Korea

    Jin-Hyun Jeong

Authors
  1. Hwan-Suck Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sae-Noon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-Hyun Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hyunsu Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hyunsu Bae.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, HS., Kim, SN., Jeong, JH. et al. A Novel Synthetic Compound 4-Acetyl-3-methyl-6-(2-bromophenyl)pyrano[3,4-c]pyran-1,8-dione Inhibits the Production of Nitric Oxide and Proinflammatory Cytokines Via the NF-κB Pathway in Lipopolysaccharide-Activated Microglia Cells. Neurochem Res 38, 807–814 (2013). https://doi.org/10.1007/s11064-013-0983-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-0983-6

Keywords

Search

Navigation