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

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 disorders^5,9 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 (K_i= 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.^27,28 To 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.

GI EFFECTS OF H₄R LIGANDS

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

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 indomethacin^57,58 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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