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Original Paper
Pharmacology 2012;89:287–294
DOI: 10.1159/000337736
Effects of Histamine H
4
Receptor Ligands
in a Mouse Model of Gastric Ulceration
Maristella Adami
a
Cristina Pozzoli
a
Alessandro Menozzi
b
Simone Bertini
b
Benedetta Passeri
b
Anna Maria Cantoni
b
Rogier Smits
c
Iwan de Esch
c
Rob Leurs
d
Gabriella Coruzzi
a
Departments of
a
Human Anatomy, Pharmacology and Forensic Medicine, and
b
Animal Health, University of Parma,
Parma, Italy;
c
Griffin Discoveries BV, and
d
Leiden/Amsterdam Center for Drug Research, Department of Medicinal
Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
gastroprotection induced by JNJ7777120 (10 mg/kg s.c.).
Conclusions: Data obtained with selective ligands suggest
that the H
4
R may have a role in mouse gastric ulcerogenesis.
If confirmed in humans, these data would emphasize the po-
tential advantage of H
4
R blockers as gastrosparing anti-in-
flammatory drugs. The lack of effects of JNJ7777120 in
C57BL/6J mice has to be carefully considered in the pharma-
cological characterization of H
4
R functions and/or new se-
lective ligands. Copyright © 2012 S. Karger AG, Basel
Introduction
There is wide evidence that the newly discovered his-
tamine H
4
receptor (H
4
R) is involved in inflammation
and allergy [1, 2]. Accordingly, H
4
R antagonists are under
development as novel anti-allergic and anti-inflammato-
ry drugs [3–5]. Following early studies, which detected
H
4
R expression primarily on cells of hematopoietic ori-
gin, the occurrence of these receptors was subsequently
reported in other peripheral tissues, including nerves of
human nasal mucosa [6], rat conjunctiva [7] and, rather
unexpectedly from early data, central neurons [8, 9]. In
rodents and in humans, H
4
R expression was detected by
immunohistochemistry in different areas and in differ-
Key Words
Histamine H
4
receptor JNJ7777120 VUF8430 VUF10460
Gastric mucosal damage Mouse strain
Abstract
Aim: In the present study we examined whether histamine
H
4
receptors (H
4
Rs) have a role in gastric ulcerogenesis using
a mouse model of gastric damage. Methods: The H
4
R an-
tagonist JNJ7777120 and the H
4
R agonists VUF8430 and
VUF10460 were investigated in fasted CD-1 mice against the
ulcerogenic effect induced by co-administration of indo-
methacin (IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/
kg i.p.). Both macroscopic and histologic lesions were exam-
ined. Strain-related differences were investigated by testing
JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. Re-
sults: Neither JNJ7777120 nor the H
4
R agonists displayed ef-
fects 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 ef-
fect 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 H
4
R 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
Received: February 14, 2012
Accepted: February 22, 2012
Published online: April 25, 2012
Prof. Gabriella Coruzzi, Section of Pharmacology
Department of Human Anatomy, Pharmacology and Forensic Medicine
University of Parma, Via Volturno 39
IT–43125 Parma (Italy)
Tel. +39 0521 903 851, E-Mail gabriella.coruzzi @ unipr.it
© 2012 S. Karger AG, Basel
0031–7012/12/0896–0287$38.00/0
Accessible online at:
www.karger.com/pha