Aim: In the present study we examined whether histamine H4 receptors (H4Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage. Methods: The H4R antagonist JNJ7777120 and the H4R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin (IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. Results: Neither JNJ7777120 nor the H4R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD-1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H4R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.). Conclusions: Data obtained with selective ligands suggest that the H4R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H4R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H4R functions and/or new selective ligands.

1.
Leurs R, Chazot PL, Shenton FC, Lim HD, de Esch IJ: Molecular and biochemical pharmacology of the histamine H4 receptor. Br J Pharmacol 2009;157:14–23.
2.
Zampeli E, Tiligada E: The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol 2009;157:24–33.
3.
Thurmond RL, Gelfand EW, Dunford PJ: The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov 2008;7:41–53.
4.
Engelhardt H, Smits RA, Leurs R, Haaksma E, de Esch IJ: A new generation of anti-histamines: histamine H4 receptor antagonists on their way to the clinic. Curr Opin Drug Discov Devel 2009;12:628–643.
5.
Smits RA, Leurs R, de Esch IJ: Major advances in the development of histamine H4 receptor ligands. Drug Discov Today 2009;14:745–753.
6.
Nakaya M, Takeuchi N, Kondo K: Immunohistochemical localization of histamine receptor subtypes in human inferior turbinates. Ann Otol Rhinol Laryngol 2004;113:552–557.
7.
Zampeli E, Thurmond RL, Tiligada E: The histamine H4 receptor antagonist JNJ7777120 induces increases in the histamine content of the rat conjunctiva. Inflamm Res 2009;58:285–291.
8.
Strakhova MI, Nikkel AL, Manelli AM, Hsieh GC, Esbenshade TA, Brioni JD, Bitner RS: Localization of histamine H4 receptors in the central nervous system of human and rat. Brain Res 2009;1250:41–48.
9.
Connelly WM, Shenton FC, Lethbridge N, Leurs R, Waldvogel HJ, Faull RL, Lees G, Chazot PL: The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br J Pharmacol 2009;157:55–63.
10.
Cianchi F, Cortesini C, Schiavone N, Perna F, Magnelli L, Fanti E, Bani D, Messerini L, Fabbroni V, Perigli G, Capaccioli S, Masini E: The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res 2005;11:6807–6815.
11.
Boer K, Helinger E, Helinger A, Pocza P, Pos Z, Demeter P, Baranyai Z, Dede K, Darvas Z, Falus A: Decreased expression of histamine H1 and H4 receptors suggests disturbance of local regulation in human colorectal tumours by histamine. Eur J Cell Biol 2008;87:227–236.
12.
Sander LE, Lorentz A, Sellge G, Coëffier M, Neipp M, Veres T, Frieling T, Meier PN, Manns MP, Bischoff SC: Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut 2006;55:498–504.
13.
Breunig E, Michel K, Zeller F, Seidl S, Weyhern CW, Schemann M: Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors. J Physiol 2007;583:731–742.
14.
Chazot PL, Shenton FC, Waldvogel H, Grandi D, Morini G: The H4 histamine receptor is expressed in both the human CNS and rodent PNS. 36th Meeting of the European Histamine Research Society, Florence, May 9–12, 2007, p 27.
15.
Morini G, Becchi G, Shenton FC, Chazot PL, Grandi D: Histamine H3 and H4 receptors are expressed on distinct endocrine cell types in the rat fundic mucosa. Inflam Res 2008;57(suppl 1):S57–S58.
16.
Jablonowski JA, Grice CA, Chai W, Dvorak CA, Venable JD, Kwok AK, Ly KS, Wei J, Baker SM, Desai PJ, Jiang W, Wilson SJ, Thurmond RL, Karlsson L, Edwards JP, Lovenberg TW, Carruthers NI: The first potent and selective non-imidazole human histamine H4 receptor antagonists. J Med Chem 2003;46:3957–3960.
17.
Thurmond RL, Desai PJ, Dunford PJ, Fung-Leung WP, Hofstra CL, Jiang W, Nguyen S, Riley JP, Sun S, Williams KN, Edwards JP, Karlsson L: A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 2004;309:404–413.
18.
Varga C, Horvath K, Berko A, Thurmond RL, Dunford PJ, Whittle BJ: Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. Eur J Pharmacol 2005;522:130–138.
19.
Dunford PJ, Varga C, Thurmond RL, Whittle BJ: Histamine H4 receptor antagonism attenuates toll-like receptor signaling and inhibits experimental colitis in the rat. Gastroenterology 2006;130:W1597.
20.
Adami M, Coruzzi G, Guaita E, De Esch IJP, Leurs R: Anti-inflammatory, analgesic and gastroprotective effects of the novel and selective histamine H4-receptor antagonist VUF5949. 34th Meeting of the European Histamine Research Society, Bled, Slovenia, May 11–14, 2005, p 47.
21.
Coruzzi G, Adami M, Pozzoli C, Smits R, de Esch I, Leurs R: Gastroprotective effects of histamine H4 receptor ligands in rodent ulcer models. Br J Pharmacol 2010;7:150P.
22.
Coruzzi G, Adami M, Pozzoli C: Role of histamine H4 receptors in the gastrointestinal tract. Front Biosci (Schol Ed) 2012;4:226–239.
23.
Rossbach K, Wendorff S, Sander K, Stark H, Gutzmer R, Werfel T, Kietzmann M, Bäumer W: Histamine H4 receptor antagonism reduces hapten-induced scratching behavior but not inflammation. Exp Dermatol 2009;18:57–63.
24.
Seike M, Furuya K, Omura M, Hamada-Watanabe K, Matsushita A, Ohtsu H: Histamine H4 receptor antagonist ameliorates chronic allergic contact dermatitis induced by repeated challenge. Allergy 2010;65:319–326.
25.
Neumann D, Beermann S, Seifert R: Does the histamine H4 receptor have a pro- or anti-inflammatory role in murine bronchial asthma? Pharmacology 2010;85:217–223.
26.
Rosethorne EM, Charlton SJ: Agonist-biased signaling at the histamine H4 receptor: JNJ7777120 recruits β-arrestin without activating G proteins. Mol Pharmacol 2011;79:749–757.
27.
Seifert R, Schneider EH, Dove S, Brunskole I, Neumann D, Strasser A, Buschauer A: 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 2011;79:631–638.
28.
Liu C, Wilson SJ, Kuei C, Lovenberg TW: Comparison of human, mouse, rat and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J Pharmacol Exp Ther 2001;299:121–130.
29.
Bell JK, McQueen DS, Rees JL: Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in BalbC mice. Br J Pharmacol 2004;142:374–380.
30.
Bäumer W, Wendorff S, Gutzmer R, Werfel T, Dijkstra D, Chazot P, Stark H, Kietzmann M: Histamine H4 receptors modulate dendritic cell migration through skin – immunomodulatory role of histamine. Allergy 2008:63:1387–1394.
31.
Coruzzi G, Pozzoli C, Adami M, Grandi D, Guido N, Smits R, de Esch IJP, Leurs R: Strain-dependent effects of the histamine H4 receptor antagonist JNJ7777120 in a murine model of acute skin inflammation. Exp Dermatol 2012;21:32–37.
32.
Coruzzi G, Adami M, Pozzoli C, de Esch IJP, Smits R, Leurs R: Selective histamine H3 and H4 receptor agonists exert opposite effects against the gastric lesions induced by HCl in the rat stomach. Eur J Pharmacol 2011;669:121–127.
33.
Lim HD, Smits RA, Bakker RA, van Dam CM, de Esch IJ, Leurs R: Discovery of S-(2-guanidylethyl)isothiourea (VUF8430) as a potent non-imidazole H4 receptor agonist. J Med Chem 2006;49:6650–6651.
34.
Rainsford KD: Gastric ulcerogenicity of non-steroidal anti-inflammatory drugs in mice with mucosa sensitized by cholinomimetic treatment. J Pharm Pharmacol 1987;39:669–672.
35.
Holzer P, Lippe IT: Stimulation of afferent nerve endings by intragastric capsaicin protects against ethanol-induced damage of gastric mucosa. Neuroscience 1988;27:981–987.
36.
Lim HD, Adami, M, Guaita E, Werfel T, Smits RA, de Esch IJ, Bakker RA, Gutzmer R, Coruzzi G, Leurs R: Pharmacological characterization of the new histamine H4 receptor agonist VUF8430. Br J Pharmacol 2009;157:34–43.
37.
Schubert ML: Gastric secretion. Curr Opin Gastroenterol 2000;16:463–468.
38.
Coruzzi G, Adami M: Peripheral actions and therapeutic potential in periphery; in Vohora D (ed): The Third Histamine Receptor: Selective Ligands as Potential Therapeutic Agents in CNS Disorders. Boca Raton, CRC Press Taylor & Francis, 2008, pp 167–209.
39.
Kitbunnadaj R, Zuiderveld OP, Christophe B, Hulscher S, Menge WM, Gelens E, Snip E, Bakker RA, Celanire S, Gillard M, Talaga P, Timmerman H, Leurs R: Identification of 4-(1H-imidazol-4(5)-ylmethyl)pyridine (immethridine) as a novel, potent, and highly selective histamine H3 receptor agonist. J Med Chem 2004;47:2414–2417.
40.
Wallace JL: Pathogenesis of NSAID-induced gastroduodenal mucosal injury. Best Pract Res Clin Gastroenterol 2001;15:691–703.
41.
Wallace JL: Prostaglandins, NSAIDs and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev 2008;88:1547–1565.
42.
Matsui H, Shimokawa O, Kaneko T, Nagano Y, Rai K, Hyodo I: The pathophysiology of non-steroidal anti-inflammatory drug (NSAID)-induced mucosal injuries in stomach and small intestine. J Clin Biochem Nutr 2011;48:107–111.
43.
Wallace JL, Keenan CM, Granger DN: Gastric ulceration induced by nonsteroidal anti-inflammatory drugs is a neutrophil-dependent process. Am J Physiol 1990;259:G462–G467.
44.
Takeshita K, Sakai K, Bacon KB, Gantner F: 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 2003;307:1072–1078.
45.
Lai LH, Chan FH: Nonsteroid anti-inflammatory drug-induced gastroduodenal injury. Curr Opin Gastroenterol 2009;25:544–548.
46.
Inagaki N, Nagao M, Igeta K, Kawasaki H, Kim JF, Nagai H: Scratching behavior in various strains of mice. Skin Pharmacol Appl Skin Physiol 2001;14:87–96.
47.
Toda S, Kimura M, Tohya K: Strain differences in histamine release from mouse peritoneal mast cells induced by compound 48/80 or A23187. Jikken Dobutsu 1989;38:135–137.
48.
You Q, Cheng L, Reilly TP, Wegmann D, Ju C: Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology 2006;44:1421–1431.
49.
Cowden JM, Zhang M, Dunford PJ, Thurmond RL: The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J Invest Dermatol 2010;130:1023–1033.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.