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The dual H3/4R antagonist thioperamide does not fully mimic the effects of the ‘standard’ H4R antagonist JNJ 7777120 in experimental murine asthma

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Abstract

Histamine is detected in high concentrations in the airways during an allergic asthma response. In a murine model of allergic asthma, the histamine H4 receptor (H4R)-selective ligand JNJ 7777120 reduces asthma-like symptoms. A sole antagonistic function of JNJ 7777120 at the murine H4R has, however, been questioned in the literature. Therefore, in the present study, we aimed at analyzing the effects of JNJ 7777120 in comparison to that of the H3/4R-selective antagonist thioperamide. Experimental murine asthma was induced by sensitization and provocation of BALB/c mice with ovalbumine (OVA). JNJ 7777120, thioperamide, or JNJ 5207852, an H3R-selective antagonist which was used to dissect H3R- and H4R-mediated activities of thioperamide, were injected subcutaneously during sensitization and effects were analyzed after provocation. Pharmacokinetic analyses revealed shortest t1/2 values in both plasma and lung tissue and lowest maximal concentration in lung tissue for JNJ 7777120 in comparison to thioperamide and JNJ 5207852. Nevertheless, JNJ 7777120 reduced serum titers of allergen-specific (anti-OVA) IgE, inflammatory infiltrations in lung tissue, and eosinophilia in bronchoalveolar lavage fluid. In contrast, thioperamide reduced only eosinophilia in bronchoalveolar lavage fluid, while anti-OVA IgE concentrations and lung infiltrations remained unaffected. JNJ 5207852 had no effect on these parameters. JNJ 7777120 provides beneficial effects in experimental murine asthma, which, however, could only partially be mimicked by thioperamide, despite more favorable pharmacokinetics. Thus, whether these effects of JNJ 7777120 are entirely attributable to an antagonistic activity at the murine H4R or whether an agonistic activity is also involved has to be reconsidered.

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References

  • Bakker RA, Timmerman H, Leurs R (2002) Histamine receptors: specific ligands, receptor biochemistry, and signal transduction. Clin Allergy Immunol 17:27–64

    PubMed  CAS  Google Scholar 

  • Barbier AJ, Berridge C, Dugovic C, Laposky AD, Wilson SJ, Boggs J, Aluisio L, Lord B, Mazur C, Pudiak CM, Langlois X, Xiao W, Apodaca R, Carruthers NI, Lovenberg TW (2004) Acute wake-promoting actions of JNJ-5207852, a novel, diamine-based H3 antagonist. Br J Pharmacol 143:649–661

    Article  PubMed  CAS  Google Scholar 

  • Beermann S, Glage S, Jonigk D, Seifert R, Neumann D (2012) Opposite effects of mepyramine on JNJ 7777120-induced amelioration of experimentally induced asthma in mice in sensitization and provocation. PLoS One 7:e30285

    Article  PubMed  CAS  Google Scholar 

  • Bonaventure P, Letavic M, Dugovic C, Wilson S, Aluisio L, Pudiak C, Lord B, Mazur C, Kamme F, Nishino S, Carruthers N, Lovenberg T (2007) Histamine H3 receptor antagonists: from target identification to drug leads. Biochem Pharmacol 73:1084–1096

    Article  PubMed  CAS  Google Scholar 

  • Cowden J, Riley J, Ma J, Thurmond R, Dunford P (2010a) Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines. Respir Res 11:86

    Article  PubMed  Google Scholar 

  • Cowden JM, Zhang M, Dunford PJ, Thurmond RL (2010b) The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J Invest Dermatol 130:1023–1033

    Article  PubMed  CAS  Google Scholar 

  • De Bie J, Henricks P, Cruikshank W, Hofman G, Jonker E, Nijkamp F, Van Oosterhout A (1998) Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5-HT receptor antagonists in a mouse model of allergic asthma. Br J Pharmacol 124:857–864

    Google Scholar 

  • Deml K-F, Beermann S, Neumann D, Strasser A, Seifert R (2009) Interactions of histamine H1-receptor agonists and antagonists with the human histamine H4-receptor. Mol Pharmacol 76:1019–1030

    Article  PubMed  CAS  Google Scholar 

  • Dunford P, O'Donnell N, Riley J, Williams K, Karlsson L, Thurmond R (2006) The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells. J Immunol 176:7062–7070

    PubMed  CAS  Google Scholar 

  • Dunford P, Williams K, Desai P, Karlsson L, McQueen D, Thurmond R (2007) Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus. J Allergy Clin Immunol 119:176–183

    Article  PubMed  CAS  Google Scholar 

  • Hartwig C, Constabel H, Neumann D, Hoymann HG, Tschernig T, Behrens GMN (2008) Impact of boostering for the strength of asthma parameters and dendritic cell numbers in a C57BL/6 model of allergic airway inflammation. Exp Toxicol Pathol 60:425–434

    Article  PubMed  Google Scholar 

  • Jutel M, Watanabe T, Klunker S, Akdis M, Thomet O, Malolepszy J, Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis C (2001) Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413:420–425

    Article  PubMed  CAS  Google Scholar 

  • Kozma G, Losonczy G, Keszei M, Komlósi Z, Buzás E, Pállinger E, Appel J, Szabó T, Magyar P, Falus A, Szalai C (2003) Histamine deficiency in gene-targeted mice strongly reduces antigen-induced airway hyper-responsiveness, eosinophilia and allergen-specific IgE. Int Immunol 15:963–973

    Article  PubMed  CAS  Google Scholar 

  • Lim H, van Rijn R, Ling P, Bakker R, Thurmond R, Leurs R (2005) Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther 314:1310–1321

    Article  PubMed  CAS  Google Scholar 

  • Ling P, Ngo K, Nguyen S, Thurmond RL, Edwards JP, Karlsson L, Fung-Leung WP (2004) Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol 142:161–171

    Article  PubMed  CAS  Google Scholar 

  • Liu C, Ma X, Jiang X, Wilson S, Hofstra C, Blevitt J, Pyati J, Li X, Chai W, Carruthers N, Lovenberg T (2001) Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol Pharmacol 59:420–426

    PubMed  CAS  Google Scholar 

  • Neumann D, Beermann S, Seifert R (2010) Does the histamine H4 receptor have a pro- or anti-inflammatory role in murine bronchial asthma? Pharmacology 85:217–223

    Article  PubMed  CAS  Google Scholar 

  • Nguyen T, Shapiro D, George S, Setola V, Lee D, Cheng R, Rauser L, Lee S, Lynch K, Roth B, O'Dowd B (2001) Discovery of a novel member of the histamine receptor family. Mol Pharmacol 59:427–433

    PubMed  CAS  Google Scholar 

  • Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El-Mays T, Vliagoftis H, Hollenberg MD, Wilson EH, Walker JK, DeFea KA (2012) β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway. Proc Natl Acad Sci U S A 109:16660–16665

    Article  PubMed  CAS  Google Scholar 

  • Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S (2000) Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem 275:36781–36786

    Article  PubMed  CAS  Google Scholar 

  • Reher TM, Neumann D, Buschauer A, Seifert R (2012) Incomplete activation of human eosinophils via the histamine H4-receptor: evidence for ligand-specific receptor conformations. Biochem Pharmacol 84:192–203

    Article  PubMed  CAS  Google Scholar 

  • Rosethorne EM, Charlton SJ (2011) Agonist-biased signaling at the histamine H4 receptor: JNJ7777120 recruits β-arrestin without activating G proteins. Mol Pharmacol 79:749–757

    Article  PubMed  CAS  Google Scholar 

  • Schnell D, Brunskole I, Ladova K, Schneider EH, Igel P, Dove S, Buschauer A, Seifert R (2011) Expression and functional properties of canine, rat, and murine histamine H4-receptors in Sf9 insect cells. Naunyn Schmiedebergs Arch Pharmacol. doi:10.1007/s00210-011-0612-3

    PubMed  Google Scholar 

  • Seifert R, Schneider EH, Dove S, Brunskole I, Neumann D, Strasser A, Buschauer A (2011) Paradoxical stimulatory effects of the “standard” histamine H4-receptor antagonist JNJ7777120: the H4-receptor joins the club of 7 transmembrane domain receptors exhibiting functional selectivity. Mol Pharmacol 79:631–638

    Article  PubMed  CAS  Google Scholar 

  • Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, Buschauer A (2013) Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 34:33–58

    Article  PubMed  CAS  Google Scholar 

  • Shen H, O'Byrne PM, Ellis R, Wattie J, Tang C, Inman MD (2002) The effects of intranasal budesonide on allergen-induced production of interleukin-5 and eotaxin, airways, blood, and bone marrow eosinophilia, and eosinophil progenitor expansion in sensitized mice. Am J Respir Crit Care Med 166:146–153

    Article  PubMed  Google Scholar 

  • Silva C, Mor M, Bordi F, Rivara S, Caretta A, Ballabeni V, Barocelli E, Plazzi PV (1997) Plasma concentration and brain penetration of the H3-receptor antagonist thioperamide in rats. Farmaco 52:457–462

    PubMed  CAS  Google Scholar 

  • Sindelar DK, Shepperd ML, Pickard RT, Alexander-Chacko J, Dill MJ, Cramer JW, Smith DP, Gadski R (2004) Central H3R activation by thioperamide does not affect energy balance. Pharmacol Biochem Behav 78:275–283

    Article  PubMed  CAS  Google Scholar 

  • Strasser A, Wittmann HJ, Buschauer A, Schneider EH, Seifert R (2013) Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs. Trends Pharmacol Sci 34:13–32

    Article  PubMed  CAS  Google Scholar 

  • Takeshita K, Bacon KB, Gantner F (2004) Critical role of L-selectin and histamine H4 receptor in zymosan-induced neutrophil recruitment from the bone marrow: comparison with carrageenan. J Pharmacol Exp Ther 310:272–280

    Article  PubMed  CAS  Google Scholar 

  • Takeshita K, Sakai K, Bacon KB, Gantner F (2003) Critical role of histamine H4 receptor in leukotriene B4 production and mast cell-dependent neutrophil recruitment induced by zymosan in vivo. J Pharmacol Exp Ther 307:1072–1078

    Article  PubMed  CAS  Google Scholar 

  • Thurmond R, Desai P, Dunford P, Fung-Leung W, Hofstra C, Jiang W, Nguyen S, Riley J, Sun S, Williams K, Edwards J, Karlsson L (2004) A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 309:404–413

    Article  PubMed  CAS  Google Scholar 

  • Venable JD, Cai H, Chai W, Dvorak CA, Grice CA, Jablonowski JA, Shah CR, Kwok AK, Ly KS, Pio B, Wei J, Desai PJ, Jiang W, Nguyen S, Ling P, Wilson SJ, Dunford PJ, Thurmond RL, Lovenberg TW, Karlsson L, Carruthers NI, Edwards JP (2005) Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine H4 antagonists. J Med Chem 48:8289–8298

    Article  PubMed  CAS  Google Scholar 

  • Westly E (2010) Nothing to sneeze at. Nat Med 16:1063–1065

    Article  PubMed  CAS  Google Scholar 

  • Zhao J, Yeong LH, Wong WS (2007) Dexamethasone alters bronchoalveolar lavage fluid proteome in a mouse asthma model. Int Arch Allergy Immunol 142:219–229

    Article  PubMed  CAS  Google Scholar 

  • Zosky G, Larcombe A, White O, Burchell J, Janosi T, Hantos Z, Holt P, Sly P, Turner D (2008) Ovalbumin-sensitized mice are good models for airway hyperresponsiveness but not acute physiological responses to allergen inhalation. Clin Exp Allergy 38:829–838

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Thomas Tschernig (Department of Anatomy, Saarland University, Saarbrücken) for his valuable help in the establishment of the murine asthma model and Dr. Klaus Resch (Institute for Pharmacology, Hannover Medical School) and Dr. Volkhard Kaever (Core Unit Mass Spectrometry—Metabolomics, Hannover Medical School) for stimulating discussions. The excellent technical assistance of Mrs. Anna Bauer and Mrs. Renate Schottmann is appreciated. This work was supported by a grant of the German Research Council (DFG SFB 587) and by the COST BMBS action BM0806.

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Authors and Affiliations

  1. Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Detlef Neumann, Silke Beermann, Christina Hartwig & Roland Seifert

  2. Core Unit Mass Spectrometry - Metabolomics, Hannover Medical School, Hannover, Germany

    Heike Burhenne

  3. Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany

    Silke Glage

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  1. Detlef Neumann
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  5. Christina Hartwig
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Correspondence to Detlef Neumann.

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Neumann, D., Beermann, S., Burhenne, H. et al. The dual H3/4R antagonist thioperamide does not fully mimic the effects of the ‘standard’ H4R antagonist JNJ 7777120 in experimental murine asthma. Naunyn-Schmiedeberg's Arch Pharmacol 386, 983–990 (2013). https://doi.org/10.1007/s00210-013-0898-4

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  • DOI: https://doi.org/10.1007/s00210-013-0898-4

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