Download PDF
Planta Med 2010; 76(2): 120-127
DOI: 10.1055/s-0029-1186005
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

6-Hydroxycleroda-3,13-dien-15,16-olide Protects Neuronal Cells from Lipopolysaccharide-Induced Neurotoxicity through the Inhibition of Microglia-Mediated Inflammation

Yu-Tzu Shih1 , Ya-Yun Hsu2 , Fang-Rong Chang1 , Yang-Chang Wu1 , Yi-Ching Lo3
  • 1Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 2Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 3Department of Pharmacology, Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Further Information

Publication History

received May 4, 2009 revised June 24, 2009

accepted July 6, 2009

Publication Date:
03 August 2009 (online)

    Permissions and Reprints

Abstract

Polyalthia longifolia var. pendula is used as an antipyretic agent in indigenous systems of medicine. Microglia-mediated inflammation plays an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases. The aim of this study was to investigate the effects of 6-hydroxycleroda-3,13-dien-15,16-olide (PL3) extracted from Polyalthia longifolia var. pendula on lipopolysaccharide(LPS)-induced inflammation in microglia-like HAPI cells and primary microglia cultures. In microglia-neuron co-cultures, LPS decreased the cell viability of neuroblastoma SH-SY5Y cells. LPS-induced cell death was attenuated by the NOS inhibitor, L-NAME, the COX-2 inhibitor, NS-398 or the NADPH oxidase inhibitor, DPI, respectively. In LPS-treated microglia cells, PL3 decreased the expression of iNOS, COX-2, gp91phox, and NF-κBp65, the degradation of IκBα, and the production of NO, PGE2, iROS, and TNF-α. PL3 also enhanced the expression of HO-1, a cytoprotective and anti-inflammatory enzyme. Moreover, PL3 reduced LPS-activated microglia-induced cell death. The present results suggest that PL3 inhibits microglia-mediated inflammation and inflammation-related neuronal cell death. Therefore, PL3 has potential use for the treatment of inflammation-related neurodegenerative diseases.

Key words

16‐hydroxycleroda‐3,13‐dien‐15,16‐olide - lipopolysaccharide - microglia - inflammation - neuroprotection - Polyalthia longifolia var. pendula (Annonaceae)

References

  • 1 Block M L, Zecca L, Hong J S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms.  Nat Rev Neurosci. 2007;  8 57-69
    CrossrefPubMedGoogle Scholar
  • 2 Kim S U, de Vellis J. Microglia in health and disease.  J Neurosci Res. 2005;  81 302-313
    Google Scholar
  • 3 Liao H, Bu W Y, Wang T H, Ahmed S, Xiao Z C. Tenascin-R plays a role in neuroprotection via its distinct domains that coordinate to modulate the microglia function.  J Biol Chem. 2005;  280 8316-8323
    PubMedGoogle Scholar
  • 4 Elkabes S, DiCicco-Bloom E M, Black I B. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function.  J Neurosci. 1996;  16 2508-2521
    PubMedGoogle Scholar
  • 5 Hurley S D, Walter S A, Semple-Rowland S L, Streit W J. Cytokine transcripts expressed by microglia in vitro are not expressed by ameboid microglia of the developing rat central nervous system.  Glia. 1999;  25 304-309
    CrossrefPubMedGoogle Scholar
  • 6 Dawson V L, Brahmbhatt H P, Mong J A, Dawson T M. Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures.  Neuropharmacology. 1994;  33 1425-1430
    CrossrefPubMedGoogle Scholar
  • 7 Chao C C, Hu S, Molitor T W, Shaskan E G, Peterson P K. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism.  J Immunol. 1992;  149 2736-2741
    PubMedGoogle Scholar
  • 8 Floyd R A. Antioxidants, oxidative stress, and degenerative neurological disorders.  Proc Soc Exp Biol Med. 1999;  222 236-245
    CrossrefPubMedGoogle Scholar
  • 9 Dickson D W, Lee S C, Mattiace L A, Yen S H, Brosnan C. Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease.  Glia. 1993;  7 75-83
    CrossrefPubMedGoogle Scholar
  • 10 Chao C C, Hu S, Peterson P K. Glia, cytokines, and neurotoxicity.  Crit Rev Neurobiol. 1995;  9 189-205
    PubMedGoogle Scholar
  • 11 Iravani M M, Leung C C, Sadeghian M, Haddon C O, Rose S, Jenner P. The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation.  Eur J Neurosci. 2005;  22 317-330
    CrossrefPubMedGoogle Scholar
  • 12 Merrill J E. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological.  Dev Neurosci. 1992;  14 1-10
    CrossrefPubMedGoogle Scholar
  • 13 Mandel S, Grunblatt E, Riederer P, Gerlach M, Levites Y, Youdim M B. Neuroprotective strategies in Parkinson's disease: an update on progress.  CNS Drugs. 2003;  17 729-762
    PubMedGoogle Scholar
  • 14 Im J Y, Kim D, Paik S G, Han P L. Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation.  Free Radic Biol Med. 2006;  41 960-972
    CrossrefPubMedGoogle Scholar
  • 15 Chen H, Zhang S M, Hernan M A, Schwarzschild M A, Willett W C, Colditz G A, Speizer F E, Ascherio A. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease.  Arch Neurol. 2003;  60 1059-1064
    CrossrefPubMedGoogle Scholar
  • 16 Tansey M G, Frank-Cannon T C, McCoy M K, Lee J K, Martinez T N, McAlpine F E, Ruhn K A, Tran T A. Neuroinflammation in Parkinson's disease: is there sufficient evidence for mechanism-based interventional therapy?.  Front Biosci. 2008;  13 709-717
    CrossrefPubMedGoogle Scholar
  • 17 Buttini M, Limonta S, Boddeke H W. Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain.  Neurochem Int. 1996;  29 25-35
    CrossrefPubMedGoogle Scholar
  • 18 Weinstein J R, Swarts S, Bishop C, Hanisch U K, Moller T. Lipopolysaccharide is a frequent and significant contaminant in microglia-activating factors.  Glia. 2008;  56 16-26
    CrossrefPubMedGoogle Scholar
  • 19 Qian L, Block M L, Wei S J, Lin C F, Reece J, Pang H, Wilson B, Hong J S, Flood P M. Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase.  J Pharmacol Exp Ther. 2006;  319 44-52
    CrossrefPubMedGoogle Scholar
  • 20 Qian L, Hong J S, Flood P M. Role of microglia in inflammation-mediated degeneration of dopaminergic neurons: neuroprotective effect of interleukin 10.  J Neural Transm Suppl. 2006;  70 367-371
    PubMedGoogle Scholar
  • 21 Block M L, Hong J S. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism.  Prog Neurobiol. 2005;  76 77-98
    CrossrefPubMedGoogle Scholar
  • 22 Khatoon S. Flora of Pakistan, Vol. 167. Karachi; Shamim Printing Press 1985: 1-15
    Google Scholar
  • 23 Chen C Y, Chang F R, Shih Y C, Hsieh T J, Chia Y C, Tseng H Y, Chen H C, Chen S J, Hsu M C, Wu Y C. Cytotoxic constituents of Polyalthia longifolia var. pendula.  J Nat Prod. 2000;  63 1475-1478
    CrossrefPubMedGoogle Scholar
  • 24 Chang F R, Hwang T L, Yang Y L, Li C E, Wu C C, Issa H H, Hsieh W B, Wu Y C. Anti-inflammatory and cytotoxic diterpenes from formosan Polyalthia longifolia var. pendula.  Planta Med. 2006;  72 1344-1347
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Lin Y C, Uang H W, Lin R J, Chen I J, Lo Y C. Neuroprotective effects of glyceryl nonivamide against microglia-like cells and 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells.  J Pharmacol Exp Ther. 2007;  323 877-887
    CrossrefPubMedGoogle Scholar
  • 26 Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann D L, Vallejo J G. In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4.  J Infect Dis. 2001;  183 1617-1624
    CrossrefPubMedGoogle Scholar
  • 27 Cheepsunthorn P, Radov L, Menzies S, Reid J, Connor J R. Characterization of a novel brain-derived microglial cell line isolated from neonatal rat brain.  Glia. 2001;  35 53-62
    CrossrefPubMedGoogle Scholar
  • 28 Sriram K, Matheson J M, Benkovic S A, Miller D B, Luster M I, O'Callaghan J P. Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha.  Faseb J. 2006;  20 670-682
    CrossrefPubMedGoogle Scholar
  • 29 Willis D, Moore A R, Frederick R, Willoughby D A. Heme oxygenase: a novel target for the modulation of the inflammatory response.  Nat Med. 1996;  2 87-90
    PubMedGoogle Scholar
  • 30 Chen K, Gunter K, Maines M D. Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death.  J Neurochem. 2000;  75 304-313
    CrossrefPubMedGoogle Scholar
  • 31 May M J, Ghosh S. Signal transduction through NF-kappa B.  Immunol Today. 1998;  19 80-88
    CrossrefPubMedGoogle Scholar
  • 32 Baeuerle P A, Baltimore D. NF-kappa B: ten years after.  Cell. 1996;  87 13-20
    CrossrefPubMedGoogle Scholar

Dr. Yi-Ching Lo

Department and Graduate Institute of Pharmacology
College of Medicine
Kaohsiung Medical University

100 Shih-Chuan 1st Road

Kaohsiung 807

Taiwan

Phone: + 88 6 73 23 46 86

Fax: + 88 6 73 23 46 86

Email: yichlo@kmu.edu.tw

      >