Open journal

ISSN 2377-8369

The Histamine H4 Receptor: A Novel Target for Safe Anti-inflammatory Drugs?

Maristella Adami* and Gabriella Coruzzi

Maristella Adami, PhD

Department of Neuroscience, University of Parma Via Volturno 39, 43125 Parma Italy, Tel. +39 0521 903943, Fax: +39 0521 903852; E-mail:


After the discovery of histamine H2 receptors and their revolutionary role in the therapy of gastroduodenal ulcer,1,2,3 the research on Gastrointestinal (GI) histamine was considered to be settled. However, renewed interested in the amine emerged in the ‘90s with the discovery of the histamine H3 receptor (H3R),4,5 and subsequently, in the early 2000 when the H4 receptor (H4R) was detected from the human genome database by several independent groups.6,7,8 As a consequence, novel therapeutic fields have been unravelled for antihistamine drugs: whereas histamine H3R antagonists may represent new therapeutic options for cognitive, sleep and memory disorders5,9 and for obesity,10 H4R antagonists are currently the object of intensive research, as potential candidates in the therapy of allergy, inflammatory disorders, neurophatic pain and pruritus.7,11,12

The present review will focus on the location and functional role of H4Rs in the GI tract and the potential clinical implications for human diseases. Beneficial effects of H4R blockers at GI level would be of particular interest, when considering that the available Nonsteroidal Anti-inflammatory Drugs (NSAIDs) are still endowed with significant gastric and intestinal toxicity.13,14 This is particularly true for the still unrecognized NSAID-induced enteropathy, which occurs frequently and still awaits for medical treatment.15,16

The histamine H4R

The H4R is a G-protein coupled receptor which has been primarily detected outside the Central Nervous System (CNS), and, in particular, in immune and inflammatory cells, including mast cells, eosinophils, basophils, dendritic cells and T cells.6,7,8 This has led to hypothesize for the H4R a key role in inflammation and immunoregulation. Indeed, a variety of in vitro data have shown that H4Rs are involved in the control of chemotactic response and cytoskeletal changes of human eosinophils, mast cell chemotaxis and release of interleukin-16 from human CD8+ T cells and dendritic cell migration.7,8,17 Functional in vivo studies in rodents have confirmed anti-inflammatory, antihyperalgesic and antiallergic effects of selective H4R antagonists in a variety of acute and chronic experimental models.18,19,20,21,22,23,24

Histamine H4R ligands

Since H3R and H4R are closely related, the early physio-pharmacological characterization of the H4R was based on compounds retaining the ability to bind the H3R subtype.25 The first selective H4R antagonist was the indolylpiperazine compound, JNJ7777120, which displayed high affinity (Ki= 4 nM) for the human H4R with and a >1000-fold selectivity over the other histamine receptors,26 thus becoming the “reference” H4R ligand in most experimental assays, also due to the lack of highly selective H4R agonists.27,28To complicate matters, the subsequent availability of chemically different H4R ligands showed that several compounds could display a protean activity, behaving as full agonists, partial agonists or actually neutral antagonists, depending on the functional assay.29,30,31,32 Indeed, some pharmacological discrepancies have recently emerged: H4R activation, rather than blockade, was found to display anti-inflammatory or protective effects,30,31,32 and on the other hand, the “standard” H4R antagonist JNJ7777120 was found to behave as an agonist in some experimental assays.29,30,31 The use of non selective compounds (i.e. mixed H3/H4 receptor ligands) and the occurrence of strain-dependent effects of H4R ligands33 may further contribute to an erroneous interpretation of experimental data and make the characterization of H4R function a great challenge for histaminologists. Human studies are therefore highly recommended. Unfortunately, so far, only few compounds have entered into clinical trials: JNJ-39758979 in phase II for itch and asthma, ZPL-38937887 (PalauPharma) in phase I, UR-63325 (PalauPharma) in phase I with excellent safety and profile.34

Location of H4Rs in the GI tract

H4R expression was found throughout the GI tract of different animal species and humans.35 As shown in Table 1, the expression was unraveled both in normal tissues and under pathological conditions, such as esophagitis and colitis;36,37,38,39,40,41,42,43,44,45,46,47,48,49 a decrease in H4R density was reported in human gastric and colorectal carcinoma.39,55,56 Cell types expressing H4R include immune and inflammatory cells, epithelial cells and neurons of the myenteric and submucous plexus. Interestingly, H4R expression was found in ghrelin-producing cells of the rat stomach,37 leading to speculation about a possible role of histamine in the secretion of the orexigenic peptide.


GOJ-1-103 table 1

H4R= H4 receptor; GI= Gastrointestinal; TNBS= Trinitrobenzene Sulphonic Acid

Table 1: Expression of histamine H4Rs in the GI tract


GI effects of H4R ligands

The functional data reported in intact animals with the available H4R antagonists are summarized in Table 2.35

GOJ-1-103 table 2

H4R= H4 receptor; GI= Gastrointestinal; TNBS= Trinitrobenzene Sulphonic Acid

Table 2: Protective effects of histamine H4R antagonists in the GI tract

In rodents the reference H4R antagonist JNJ7777120 was unable to damage the gastric mucosa per se, even at the highest anti-inflammatory doses and, actually, it was able to reduce the gastric damage induced by indomethacin57,58 in two models which are widely used to unravel either gastric damage or protection.13 The gastroprotection induced by H4R blockade was unrelated to antisecretory effects or alteration in GI motility;35 moreover, it was found to differ from that induced by activation of H3Rs, since it was not evidenced against necrotizing agents, such as concentrated acid.68 Indeed, the extensive damage induced by concentrated acid (>0.35 N) is only prevented by “true” cytoprotective drugs,

like prostaglandins14 or by mechanisms activating cellular defense, such as re-epithelization and cell proliferation.69 It is thus more plausible to hypothesize a selective interference of H4R antagonists in the widely recognized mechanism underlying NSAID-induced gastric damage, i.e. accumulation and activation of neutrophils in the gastric microvasculature.70 In line with this, in several experimental models of intestinal damage, H4R antagonists were able to reduce neutrophil infiltration in intestinal mucosa.19,21,24,62,63,64

The gastric safety of H4R antagonists could be of major interest, when considering that the available anti-inflammatory drugs are still endowed with gastric toxicity;14 nevertheless, the precise role of H4R in the gastric mucosa remains to be proven, since data with selective ligands are intriguing: the H4R agonist VUF843028 was paradoxically as effective as the antagonist JNJ7777120 in reducing indomethacin-induced lesions in the rat.57

The protective effect reported by Varga et al.59 in a model of acute colitis induced by Trinitrobenzene Sulphonic Acid (TNBS) seems deemed of interest, when considering that this model resembles the human Crohn’s disease under macroscopic, histopathological and immunological aspects.71 In this assay, JNJ7777120 was able to reduce macroscopic damage, neutrophil infiltration and the production of both Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-6 (IL-6), two cytokines that play a critical role in the pathogenesis of human disease.59,60 Several groups have underlined the increase in histamine content in mucosal biopsies from Crohn’s disease, Ulcerative Colitis (UC) and food allergy;72,73 moreover, mast cells in colonic mucosal biopsies from IBS patients were found to release more histamine than in normal subjects.73 The recent observation that histamine H4Rs, together with H1Rs, contribute to the postinflammatory visceral sensitivity in the TNBS-induced colitis assay,67 leads to hypothesize that H4R antagonists may be of therapeutic value in various pathological conditions with abdominal pain.

Finally, a possible role of histamine H4Rs in cancer has been recently reviewed.74 Recent studies have evidenced the presence of H4Rs in gastric and colorectal tumor cells and a reduction of H4R density has been observed, which parallels the cancer progression.54,55,56 However, functional data with histamine and H4R ligands are contradictory, with both stimulation and/or inhibition of cell proliferation and cell growth being observed.74


The protective effects displayed by some H4R antagonists in a variety of experimental in vivo models suggest that histamine H4R blockade is not deleterious for the GI tract and can actually activate gastric and intestinal mucosal defense mechanisms, at least in rodents. Despite these favourable premises, H4R pharmacology is still intriguing and clinical studies are mandatory in order to assess the potential benefit of H4R antagonists in human GI disease. A careful validation of experimental assays, ligand selectivity and antibody specificity is of key importance to unravel the location and functional role of H4Rs in the GI tract, and the therapeutic value of drugs targeting this receptor in the human pathology.


The work is part of the EU FP7 COST Action BM0806: Recent advances in histamine receptor H4R research.

1. Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H2-receptors. Nature. 1972; 236: 385-390. doi: 10.1038/236385a0

2. Feldman M, Burton ME. Histamine2-receptor antagonists. Standard therapy for acid-peptic diseases. First part. N Engl J Med. 1990; 323: 1672-1680. doi: 10.1056/NEJM199012133232405

3. Feldman M, Burton ME. Histamine2-receptor antagonists. Standard therapy for acid-peptic diseases. Second part. N Engl J Med. 1990; 323: 1749-1755. doi: 10.1056/NEJM199012203232507

4. Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptors. Nature. 1983; 302: 832-837. doi: 10.1038/302832a0

5. Vohora D. The third Histamine Receptor: Selective Ligands as Potential Therapeutic Agents in CNS Disorders. Boca Raton, FL (USA); CRC Press, Taylor and Francis Group; 2008.

6. 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. doi: 10.1111/j.1476-5381.2009.00250.x

7. Zampeli E, Tiligada E. The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol. 2009; 157: 24-33. doi: 10.1111/j.1476-5381.2009.00151.x

8. Stark H. Histamine H4 receptor: a novel target in immunoregulation and inflammation. London, Great Britain; Versita Ltd; 2013.

9. Celanire S, Wijtmans M, Talaga P, Leurs R, de Esch IJ. Keynote review: histamine H3 receptor antagonists reach out for the clinic. Drug Discov Today. 2005; 10: 1613-1627. doi: 10.1016/S1359-6446(05)03625-1

10. Passani MB, Blandina P, Torrealba F. The histamine H3 receptor and eating behaviour. J Pharmacol Exp Ther. 2011; 336: 24-29. doi: 10.1124/jpet.110.171306

11. 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. doi: 10.1038/nrd2465

12. 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.

13. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev. 2008; 88: 1547-1565. doi: 10.1152/physrev.00004.2008

14. Wallace JL. COX-2: a pivotal enzyme in mucosal protection and resolution of inflammation. Scientific World Journal. 2006; 6: 577-588.doi:

15. Whittle BJ. Mechanisms underlying intestinal injury induced by anti-inflammatory COX inhibitors. Eur J Pharmacol. 2004; 500: 427-439. doi: 10.1016/j.ejphar.2004.07.042

16. Wallace JL. Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World J Gastroenterol. 2013; 19: 1861-1876. doi: 10.3748/wjg.v19.i12.1861

17. Zhang M, Thurmond RL, Dunford PJ. The histamine H4 receptor: a novel modulator of inflammatory and immune disorders. Pharmacol Ther. 2007; 113: 594-606. doi: 10.1016/j.pharmthera.2006.11.008

18. Strakhova MI, Cuff CA, Manelli AM, et al. In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties. Br J Pharmacol. 2009; 157: 44-54. doi: 10.1111/j.1476-5381.2009.00236.x

19. 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. doi: 10.1124/jpet.103.057489

20. Bell JK, McQueen DS, Rees JL. Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in Balb C mice. Br J Pharmacol. 2004; 142: 374-380. doi: 10.1038/sj.bjp.0705754

21. Thurmond RL, Desai PJ, Dunford PJ, et al. A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther. 2004; 309: 404-413. doi: 10.1124/jpet.103.061754

22. Coruzzi G, Adami M, Guaita E, de Esch IJ, Leurs R. Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur J Pharmacol. 2007; 563: 240-244.doi: 10.1016/j.ejphar.2007.02.026

23. Ahmad SF, Zoheir KM, Abdel-Hamied HE, et al. The role of a histamine 4 receptor as an anti-inflammatory target in carrageenan-induced pleurisy in mice. Immunology. 2014; Jan 25. doi: 10.1111/imm.12257.

24. Hsieh GC, Chandran P, Salyers AK, et al. H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats. Pharmacol Biochem Behav. 2010; 95: 41-50. doi: 10.1016/j.pbb.2009.12.004

25. de Esch IJ, Thurmond RL, Jongejan A, Leurs R. The histamine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol Sci. 2005; 26: 462-469. doi:

26. Jablonowski JA, Grice CA, Chai W, et al. The first potent and selective non-imidazole human histamine H4 receptor antagonists. J Med Chem. 2003; 46: 3957-3960. doi: 10.1021/jm0341047

27. Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R. 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. 2005; 314: 1310-1321. doi: 10.1124/jpet.105.087965

28. Lim HD, Smits RA, Bakker RA, van Dam CM, de Esch IJ, Leurs R. Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole H4 receptor agonist. J Med Chem. 2006; 49: 6650-6651. doi: 10.1021/jm060880d

29. 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. doi: 10.1124/mol.110.068395

30. Seifert R, Schneider EH, Dove S, et al. 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. doi: 10.1124/mol.111.071266

31. 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. doi: 10.1159/000285088

32. Adachi N, Liu K, Motoki A, Nishibori M, Arai T. Suppression of ischemia/reperfusion liver injury by histamine H4 receptor stimulation in rats. Eur J Pharmacol. 2006; 544: 181-187. doi: 10.1016/j.ejphar.2006.06.053

33. Coruzzi G, Pozzoli C, Adami M, et al. Strain-dependent effects of the histamine H4 receptor antagonist JNJ7777120 in a murine model of acute skin inflammation. Exp Dermatol. 2012: 21: 32-37. doi: 10.1111/j.1600-0625.2011.01396.x

34. Schreeb A, Lazewska D, Dove S, Buschauer A, Kiec-Kononowicz K, Stark H. Histamine H4 receptor ligands. In: Stark H, ed. Histamine H4 receptor: a novel drug target in immunoregulation and inflammation. London, Great Britain: Versita Ltd; 2013: 21-61.

35. Coruzzi G, Adami M, Pozzoli C. Role of histamine H4 receptors in the gastrointestinal tract. Front Biosci. 2012; 4: 226-239. doi: 10.2741/264

36. Yu S, Stahl E, Li Q, Ouyang A. Antigen inhalation induces mast cells and eosinophils infiltration in the guinea pig esophageal epithelium involving histamine-mediated pathway. Life Sci. 2008; 82: 324-330. doi: 10.1016/j.lfs.2007.12.002

37. 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. Inflamm Res. 2008; 57(Suppl. 1): S57-S58. doi: 10.1007/s00011-007-0628-9

38. Liu C, Ma X, Jiang X, Wilson SJ, Hofstra CL, Blevitt J. Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol Pharmacol. 2001; 59: 420-426. doi: 10.1124/mol.59.3.420

39. Zhang C, Xiong Y, Li J, et al. Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression. PLoS One. 2012; 7: e31207. doi: 10.1371/journal.pone.0031207

40. Takagaki K, Osawa S, Horio Y, et al. Cytokine responses of intraepithelial lymphocytes are regulated by histamine H2 receptor. J Gastroenterol. 2009; 44: 285-296. doi: 10.1007/s00535-009-0019-9

41. Chazot PL, Shenton FC, Waldvogel H, Grandi D, Morini G. The H4 histamine receptor is expressed in both the human CNS and rodent PNS. In: European Histamine Research Society, 36th Annual Meeting, Florence (Italy), May 9-12th, 2007: 27.

42. Jiang W, Lim HD, Zhang M, et al. Cloning and pharmacological characterization of the dog histamine H4 receptor. Eur J Pharmacol. 2008; 592: 26-32. doi: 10.1016/j.ejphar.2008.06.095

43. Nakamura T, Itadani H, Hidaka Y, Ohta M, Tanaka K. Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem Biophys Res Commun. 2000; 279: 615-620.doi: 10.1006/bbrc.2000.4008

44. Oda T, Morikawa N, Saito Y, Masuho Y, Matsumoto S. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes. J Biol Chem. 2000; 275: 36781-36786. doi: 10.1074/jbc.M006480200

45. Cogè F, Guenin SP, Rique H, Boutin JA, Galizzi JP. Structure and expression of the human histamine H4-receptor gene. Biochem Biophys Res Commun. 2001; 284: 301-309. doi: 10.1006/bbrc.2001.4976

46. Morse KL, Behan J, Laz TM, et al. Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther. 2001; 296: 1058-1066.

47. Sander LE, Lorentz A, Sellge G, et al. Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut. 2006; 55: 498-504. doi: 10.1136%2Fgut.2004.061762

48. Kumawat AK, Gotlind YY, Fredin MF, Willen R, Strid H, Hultgren-Hornquist E. Expression patterns of histamine receptors in the Gαi2-deficient mouse model of colitis. Inflamm Res. 2010; 59(Suppl. 4): S358-S359. doi: 10.1007/s00011-010-0263-8

49. Sutton TL, Zhao A, Madden KB, et al. Antiinflammatory mechanisms of enteric Heligmosomoides polygyrus infection against trinitrobenzene sulfonic acid-induced colitis in a murine model. Infect Immun. 2008; 76: 4772-4782. doi: 10.1128/IAI.00744-07

50. Eisenschenk MNC, Torres SM, Oliveira S, Been CS. The expression of histamine H4 receptor mRNA in the skin and other tissues of normal dogs. Vet Dermatol. 2011; 22: 396-400. doi: 10.1111/j.1365-3164.2011.00959.x

51. Oda T, Matsumoto S, Masuho Y, et al. cDNA cloning and characterization of porcine histamine H4 receptor. Biochim Biophys Acta. 2002; 1575: 135-138. doi: 10.1016/S0167-4781(02)00236-1

52. Oda T, Matsumoto S, Matsumoto M, et al. Molecular cloning of monkey histamine H4 receptor. J Pharmacol Sci. 2005; 98: 319-322. doi: 10.1254/jphs.SC0050033

53. Kim H, Dwyer L, Song JH, et al. Identification of histamine receptors and effects of histamine on murine and simian colonic excitability. Neurogastroenterol Motil. 2011; 23: e949-e409. doi: 10.1254/jphs.SC0050033

54. Cianchi F, Cortesini C, Schiavone NF, et al. 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. doi: 10.1158/1078-0432.CCR-05-0675

55. Boer K, Helinger E, Helinger A, et al. 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. doi: 10.1016/j.ejcb.2007.12.003

56. Fang Z, Yao W, Xiong Y, et al. Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression. BMC Cancer. 2011; 11: 195-205. doi: 10.1186/1471-2407-11-195

57. Coruzzi G, Adami M, Pozzoli C, Smits R, de Esch IJP, Leurs R. Gastroprotective effects of histamine H4 receptor li gands in rodent ulcer models. Br J Pharmacol. 2010; 7: 150P.

58. Adami M, Pozzoli C, Menozzi A, et al. Effects of histamine H4 receptor ligands in a mouse model of gastric ulceration. Pharmacology. 2012; 89: 287-294.doi: 10.1159/000337736

59. 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. doi: 10.1016/j.ejphar.2005.08.045

60. 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: A-689.

61. Fogel WA, Jochem J, Lewinski A. Influence of the H3/H4 receptor antagonist, thioperamide on regional haemodinamics in rats with trinitrobenzene sulfonic acid-induced colitis. Inflamm Res. 2007; 56 (Suppl. 1): S21-S22. doi: 10.1007/s00011-006-0510-1

62. Cowart MD, Altenbach RJ, Liu H, et al. Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models. J Med Chem. 2008; 51: 6547-6557. doi: 10.1021/jm800670r

63. Liu H, Altenbach RJ, Carr TL, et al. cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia. J Med Chem. 2008; 51: 7094-7098. doi: 10.1021/jm8007618

64. Strakhova MI, Cuff CA, Manelli AM, et al. In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties. Br J Pharmacol. 2009; 157: 44-54. doi: 10.1111/j.1476-5381.2009.00236.x

65. Medina V, Cricco G, Mohamad N, et al. Histamine is a selective protector against cellular damage produced by ionizing radiation. Inflamm Res. 2005; 54(Suppl. 1): S17-S18. doi: 10.1007/s00011-004-0407-9

66. Ghizzardi P, Gobbetti T, Bertoni S, et al. Histamine H4 receptor antagonism and mesenteric ischemia/reperfusion injury in mice. Gastroenterology. 2009; 136 (Suppl. 1): A-397. doi:

67. Deiteren A, De Man JG, Ruyssers NE, Moreels TG, Pelckmans PA, De Winter BY. Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity. Gut. 2014; Feb 21. doi: 10.1136/gutjnl-2013-305870.

68. Coruzzi G, Adami M, Pozzoli C, de Esch IJ, Smits R, Leurs R. Selective histamine H3 and H4 receptor agonists exert opposite effects against the gastric lesions induced byHCl in the rat stomach. Eur J Pharmacol. 2011; 669: 121-127. doi: 10.1016/j.ejphar.2011.07.038

69. 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. New York, NY, USA: CRC Press, Taylor and Francis Group; 2008: 167-209.

70. 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. doi: 10.1152/ajpgi.1990.259.3.g462

71. Elson CO, Sartor RB, Tennyson GS, Riddell RH. Experimental models of inflammatory bowel disease. Gastroenterology. 1995; 109: 1344-1367. doi:

72. Raithel M, Matek M, Baenkler HW, Jorde W, Hahn EG. Mucosal histamine content and histamine secretion in Crohn’s disease, ulcerative colitis and allergy enteropathy. Int Arch Allergy Immunol. 1995; 108: 127-133. doi: 10.1159/000237129

73. Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004; 126: 693-702.doi:

74. Medina VA, Coruzzi G, Martinal Lamas DJ, et al. Histamine in cancer. In: Stark H ed. Histamine H4 receptor: a novel drug target in immunoregulation and inflammation. London, Great Britain, Versita Ltd. 2013; 259-308.


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