title: Anti-inflammatory effects of adenosine N1-oxide.
abstract: BACKGROUND
  Adenosine is a potent endogenous anti-inflammatory and immunoregulatory molecule. Despite its promise, adenosine's extremely short half-life in blood limits its clinical application. Here, we examined adenosine N1-oxide (ANO), which is found in royal jelly. ANO is an oxidized product of adenosine at the N1 position of the adenine base moiety. We found that it is refractory to adenosine deaminase-mediated conversion to inosine. We further examined the anti-inflammatory activities of ANO in vitro and in vivo.
  
  
  METHODS
  The effect of ANO on pro-inflammatory cytokine secretion was examined in mouse peritoneal macrophages and the human monocytic cell line THP-1, and compared with that of adenosine, synthetic adenosine receptor (AR)-selective agonists and dipotassium glycyrrhizate (GK2). The anti-inflammatory activity of ANO in vivo was examined in an LPS-induced endotoxin shock model in mice.
  
  
  RESULTS
  ANO inhibited secretion of inflammatory mediators at much lower concentrations than adenosine and GK2 when used with peritoneal macrophages and THP-1 cells that were stimulated by LPS plus IFN-γ. The potent anti-inflammatory activity of ANO could not be solely accounted for by its refractoriness to adenosine deaminase. ANO was superior to the synthetic A1 AR-selective agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), A2A AR-selective agonist, 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamideadenosine hydrochloride (CGS21680), and A3 AR-selective agonist, N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA), in suppressing the secretion of a broad spectrum of pro-inflammatory cytokines by peritoneal macrophages. The capacities of ANO to inhibit pro-inflammatory cytokine production by THP-1 cells were comparable with those of CCPA and IB-MECA. Reflecting its potent anti-inflammatory effects in vitro, intravenous administration of ANO significantly reduced lethality of LPS-induced endotoxin shock. A significant increase in survival rate was also observed by oral administration of ANO. Mechanistic analysis suggested that the up-regulation of the anti-inflammatory transcription factor c-Fos was, at least in part, involved in the ANO-induced suppression of pro-inflammatory cytokine secretion.
  
  
  CONCLUSIONS
  Our data suggest that ANO, a naturally occurring molecule that is structurally close to adenosine but is functionally more potent, presents potential strategies for the treatment of inflammatory disorders.
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Keizo
authors: K
authors: Kohno
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Emiko
authors: E
authors: Ohashi
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Osamu
authors: O
authors: Sano
authors: Functional Dye Division, Functional Dye Department, Hayashibara Co., Ltd, Okayama, Japan.
authors: Hajime
authors: H
authors: Kusano
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Toshio
authors: T
authors: Kunikata
authors: Applied Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Norie
authors: N
authors: Arai
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Toshiharu
authors: T
authors: Hanaya
authors: Functional Dye Division, Functional Dye Department, Hayashibara Co., Ltd, Okayama, Japan.
authors: Toshio
authors: T
authors: Kawata
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Tomoyuki
authors: T
authors: Nishimoto
authors: Core Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.|Applied Technology Division, Research and Development Center, Hayashibara Co., Ltd, Okayama, Japan.
authors: Shigeharu
authors: S
authors: Fukuda
keywords: Adenosine; Adenosine receptor agonists; Anti-inflammatory effect; Endotoxin shock; Pro-inflammatory cytokines
references: Pharmacol Ther. 2008 Jan;117(1):123-40
references: 18029023
references: Curr Top Med Chem. 2003;3(4):413-26
references: 12570759
references: J Exp Med. 1994 May 1;179(5):1437-44
references: 8163930
references: Expert Opin Emerg Drugs. 2011 Dec;16(4):597-602
references: 22148938
references: Chest. 1997 Dec;112(6 Suppl):321S-329S
references: 9400897
references: J Exp Med. 1993 Apr 1;177(4):1205-8
references: 8459215
references: Biosci Biotechnol Biochem. 2004 Jan;68(1):138-45
references: 14745176
references: J Pharmacol Exp Ther. 2006 Jan;316(1):71-8
references: 16188954
references: J Agric Food Chem. 2004 Jan 14;52(1):15-20
references: 14709007
references: J Leukoc Biol. 2008 Mar;83(3):447-55
references: 18160539
references: Arthritis Rheum. 2003 Jan;48(1):240-7
references: 12528125
references: J Immunol. 2010 Oct 1;185(7):4374-84
references: 20729330
references: Immunity. 2009 Mar 20;30(3):372-83
references: 19285436
references: Eur J Pharmacol. 1998 Oct 9;358(3):261-8
references: 9822893
references: ScientificWorldJournal. 2011 Feb 03;11:320-39
references: 21298223
references: Drugs. 2012 Oct 1;72(14):1867-80
references: 22938141
references: J Clin Biochem Nutr. 2012 Jan;50(1):59-66
references: 22247602
references: Int Immunol. 2006 May;18(5):671-7
references: 16569682
references: Sci Signal. 2009 Jun 16;2(75):ra28
references: 19531803
references: PLoS One. 2012;7(2):e32416
references: 22389701
references: Eur J Pharmacol. 1983 Sep 16;93(1-2):21-6
references: 6628545
references: Trends Immunol. 2004 Jan;25(1):33-9
references: 14698282
references: Biochem Pharmacol. 1999 Jan 1;57(1):65-75
references: 9920286
references: Eur J Pharmacol. 2007 Feb 5;556(1-3):144-50
references: 17173893
references: Ann Rheum Dis. 2001 Aug;60(8):729-35
references: 11454634
references: J Pharmacol Exp Ther. 2009 Dec;331(3):1051-61
references: 19749080
references: Int Immunopharmacol. 2003 Sep;3(9):1313-24
references: 12890429
references: Biosci Biotechnol Biochem. 2006 Apr;70(4):897-906
references: 16636457
references: Br J Pharmacol. 2012 Aug;166(7):2070-83
references: 22352763
references: J Immunol. 2010 May 1;184(9):5271-9
references: 20348420
references: J Immunol. 1993 Jul 1;151(1):389-96
references: 8326132
references: Nucleic Acids Res. 2006 Feb 14;34(3):e27
references: 16478713
references: Cytokine. 2006 Jul;35(1-2):95-9
references: 16963274
references: Curr Top Med Chem. 2010;10(9):902-22
references: 20370660
references: Int J Biol Sci. 2012;8(9):1227-36
references: 23136551
references: IUBMB Life. 2012 Jan;64(1):48-55
references: 22095907
references: In Vivo. 2008 Sep-Oct;22(5):583-6
references: 18853750
references: BioDrugs. 2010 Dec 14;24 Suppl 1:3-14
references: 21175228
references: Nat Rev Drug Discov. 2008 Sep;7(9):759-70
references: 18758473
references: Acta Pharmacol Sin. 2010 Sep;31(9):1133-40
references: 20711219
references: PLoS One. 2008 May 07;3(5):e2107
references: 18461129
references: Endocr Metab Immune Disord Drug Targets. 2008 Dec;8(4):244-54
references: 19075778