Effect of histamine H4 receptor antagonist on allergic rhinitis in mice
Introduction
Allergic rhinitis is the most common immune-mediated disease, and the main symptoms are sneezing, pruritis, rhinorrhea and nasal obstruction. The pathogenesis of the nasal allergic reaction initially involves the interaction of allergens with a specific IgE antibody bound to the surface of mast cells and basophils on the nasal mucosa [1], [2]. As a result, many symptoms associated with allergic rhinitis are caused by the release of mediators, including histamine, leukotoriene, thromboxane A2 and cytokines, from mast cells [3], [4].
Histamine is one of the most important chemical mediators of allergy and inflammation [5], [6], and plays an important role in eliciting nasal symptoms of allergic rhinitis, such as sneezing, itch, rhinorrhea and nasal obstruction [7], [8]; therefore, histamine H1 receptor antagonists, such as chlorpheniramine and ketotifen, have been used as the first choice in the treatment of nasal allergy. We have reported that histamine H1 receptor antagonists inhibited nasal symptoms induced by antigen–antibody reaction in rats and mice [9], [10]; however, it has been pointed out that these histamine H1 receptor antagonists did not completely inhibit nasal symptoms [11].
Recently, a novel histamine receptor, histamine H4 receptor has been identified [12], [13], [14], [15], [16]. Histamine H4 receptor is expressed by immunologically relevant tissues, such as spleen and thymus, and mast cells and leukocytes, such as eosinophils; therefore, histamine H4 receptor is considered to exhibit immunomodulatory functions [14], [15], [16], [17]. Chemotaxis and calcium mobilization of mast cells were considered important mechanisms for the action of histamine H4 receptor [18]. In in vivo studies, histamine H4 receptor antagonist, JNJ7777120, has also been shown to be important in allergic inflammation [19], [20]. Consequently, clarification of the relationship between histamine H4 receptor and allergic disease, such as allergic rhinitis is eagerly anticipated; however, the role of histamine H4 receptor in allergic rhinitis is still uncertain. The present study was therefore undertaken to clarify the effect of histamine H4 receptor antagonist, JNJ7777120, using a mouse allergic rhinitis model.
Section snippets
Animals
Five-week-old female BALB/c mice were obtained from Japan SLC (Shizuoka, Japan). The animals were housed in an air-conditioned room with controlled temperature (24 ± 2 °C) and humidity (50 ± 15%). Food and water were given ad libitum. The number of animals for nasal symptoms and serum total IgE tests was 8 animals, and the number of animals for cytokine production test was 6 animals. All procedures involving animals were conducted in accordance with the guidelines for Animal Experiments at Okayama
Effects of JNJ7777120 and ketotifen on nasal symptoms by intranasal administration
Fig. 2 shows the effects of histamine H4 receptor antagonist, JNJ7777120, and histamine H1 receptor antagonist, ketotifen, by intranasal administration on nasal symptoms induced by antigen. Sneezing and nasal rubbing in the control group increased gradually depending on daily intranasal sensitization. In addition, JNJ7777120 dose-dependently inhibited nasal symptoms by single administration and repeated administration for a week. Significant effects were observed at a dose of 10 nmol/site by
Discussion
It was found that a histamine H4 receptor antagonist, JNJ7777120, significantly inhibited nasal symptoms induced by antigen application by single intranasal administration. Dunford et al. [22] also reported that oral administration of JNJ7777120 inhibited scratching behavior induced by histamine and histamine H4 receptor agonist. From these findings, it is reasonable to presume that JNJ7777120 is effective in an immediate allergic reaction mediated mainly by histamine. JNJ7777120 is reported to
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