Gastro

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: maristella.adami@unipr.it

Introduction

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

Conclusions

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.

Acknowledgements

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

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