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

Maristella Adami, Gabriella Coruzzi

Department of Neuroscience, University of Parma, Via Volturno 39, 43125 Parma, ItalyItaly
Department of Neuroscience, University of Parma, Via Volturno 39, 43125 Parma, Italy (retired)

DOI: https://doi.org/10.17140/goj-1-103 · Published 2014-07-16 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2014 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Keywords: Histamine H4 receptor; Stomach; Intestine

Introduction

After the discovery of histamine H2 receptors and their revolutionary role in the ther-

1-3 apy of gastroduodenal ulcer,1-3 the research on Gastrointestinal (GI) histamine was considered

to be settled. However, renewed interested in the amine emerged in the ‘90s with the discovery

4,5 of the histamine H3 receptor (H3R),4,5 and subsequently, in the early 2000 when the H4 receptor

6-8 (H4R) was detected from the human genome database by several independent groups.6-8 As a

consequence, novel therapeutic fields have been unravelled for antihistamine drugs: where-

as histamine H3R antagonists may represent new therapeutic options for cognitive, sleep and

5,9 10 memory disorders and for obesity, H4R antagonists are currently the object of intensive

research, as potential candidates in the therapy of allergy, inflammatory disorders, neurophatic

7,11,12

tract and the potential clinical implications for human diseases. Beneficial effects of H4R block-

toxicity. This is particularly true for the still unrecognized NSAID-induced enteropathy, 15-16 which occurs frequently and still awaits for medical treatment.

The Histamine H R

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.6-8 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 den-

7-8,17 dritic cell migration. Functional in vivo studies in rodents have

confirmed anti-inflammatory, antihyperalgesic and antiallergic ef-

fects of selective H4R antagonists in a variety of acute and chronic

18-24 experimental models.

Histamine H4R Ligands

Since H3R and H4R are closely related, the early physio-

pharmacological characterization of the H4R was based on com-

pounds 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 his-

tamine receptors,26 thus becoming the “reference” H4R ligand in

most experimental assays, also due to the lack of highly selective

27,28 H4R agonists. To complicate matters, the subsequent availabil-

ity of chemically different H R ligands showed that several com-

pounds could display a protean activity, behaving as full agonists,

partial agonists or actually neutral antagonists, depending on the

29-32 functional assay. Indeed, some pharmacological discrepancies

have recently emerged: H4R activation, rather than blockade, was

found to display anti-inflammatory or protective effects, and

on the other hand, the “standard” H4R antagonist JNJ7777120 was

found to behave as an agonist in some experimental assays.

The use of non selective compounds (i.e. mixed H3/H4 receptor

ligands) and the occurrence of strain-dependent effects of H4R li-

gands33 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.

LOCATION OF H4Rs IN THE GI TRACT

H4R expression was found throughout the GI tract of

different animal species and humans. As shown in Table 1,

the expression was unraveled both in normal tissues and under

pathological conditions, such as esophagitis and colitis; a de-

crease in H4R density was reported in human gastric and colorec-

39,55-56 tal carcinoma. Cell types expressing H4R include immune

and inflammatory cells, epithelial cells and neurons of the my-

enteric and submucous plexus. Interestingly, H4R expression was

Gastro

speculation about a possible role of histamine in the secretion

of the orexigenic peptide.

6-8 H4R= H4 receptor; GI= Gastrointestinal; TNBS= Trinitrobenzene Sulphonic Acid

Table 1. Expression of histamine H4Rs in the GI tract

Gi Effects Of H R Ligands

The functional data reported in intact animals with

the available H4R antagonists are summarized in Table 2.

30-32

29-31

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

34 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 57,58 35 reduce the gastric damage induced by indomethacin in

two models which are widely used to unravel either gastric

36-49 damage or protection. The gastroprotection induced by H4R

blockade was unrelated to antisecretory effects or alteration

in GI motility; 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. In-

deed, the extensive damage induced by concentrated acid

like prostaglandins or by mechanisms activating cellular de-

fense, such as re-epithelization and cell proliferation. It is thus

more plausible to hypothesize a selective interference of H R

antagonists in the widely recognized mechanism underlying

NSAID-induced gastric damage, i.e. accumulation and activa-

tion of neutrophils in the gastric microvasculature. In line with

this, in several experimental models of intestinal damage, H4R

antagonists were able to reduce neutrophil infiltration in intesti-

19,21,24,62-64 nal mucosa.

The gastric safety of H R antagonists could be of major

interest, when considering that the available anti-inflammatory

drugs are still endowed with gastric toxicity; nevertheless, the

precise role of H4R in the gastric mucosa remains to be proven,

since data with selective ligands are intriguing: the H R ago-

28 4 nist VUF8430 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. in a mod-

el 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 macroscop-

ic, histopathological and immunological aspects. 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. Several

groups have underlined the increase in histamine content in mu-

cosal biopsies from Crohn’s disease, Ulcerative Colitis (UC)

72-73 and food allergy; moreover, mast cells in colonic mucosal

biopsies from IBS patients were found to release more histamine

than in normal subjects. The recent observation that histamine

H Rs, together with H Rs, contribute to the postinflammatory 4 1

visceral sensitivity in the TNBS-induced colitis assay,67 leads to

hypothesize that H R antagonists may be of therapeutic value in

various pathological conditions with abdominal pain.

Finally, a possible role of histamine H Rs in cancer

has been recently reviewed.74 Recent studies have evidenced

the presence of H Rs in gastric and colorectal tumor cells and

a reduction of H R density has been observed, which parallels

4 54,55,56 the cancer progression. However, functional data with his-

tamine and H4R ligands are contradictory, with both stimulation

and/or inhibition of cell proliferation and cell growth being ob-

served.

Conclusions

The protective effects displayed by some H4R an-

tagonists in a variety of experimental in vivo models sug-

gest 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 fa-

vourable premises, H4R pharmacology is still intriguing and

Gastro

clinical studies are mandatory in order to assess the potential

69 benefit of H R antagonists in human GI disease. A careful vali-

dation of experimental assays, ligand selectivity and antibody

specificity is of key importance to unravel the location and func-

tional role of H4Rs in the GI tract, and the therapeutic value of

70 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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