Effects of Histamine H₄ Receptor Ligands in a Mouse Model of Gastric Ulceration

Abstract

Aim: In the present study we examined whether histamine H₄ receptors (H₄Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage. Methods: The H₄R antagonist JNJ7777120 and the H₄R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin (IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. Results: Neither JNJ7777120 nor the H₄R agonists displayed effects 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 effect 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 H₄R 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 gastroprotection induced by JNJ7777120 (10 mg/kg s.c.). Conclusions: Data obtained with selective ligands suggest that the H₄R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H₄R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H₄R functions and/or new selective ligands.

Histamine H4 receptors in the gastrointestinal tract

“…In addition, enhanced chemically induced mucosal damage by H 4 receptor agonists could be prevented by concomitant H 4 receptor antagonists and vice versa (Coruzzi et al ., 2009; 2011). However, the findings are not fully consistent as the H 4 receptor agonists VUF8430 and VUF10460 had no effect on indomethacin/bethanecol‐induced lesions in a mouse model whereas the HCl‐induced damage in rats was enhanced by both agonists, and in contrast, indomethacin‐induced ulcerations were reduced by VUF10460 (Coruzzi et al ., 2009; 2011; Adami et al ., ). It was hypothesized that species and strain differences might contribute to the differential effects as JNJ7777120 effectively reduced indomethacin/bethanecol‐induced lesions in CD‐1, NMRI and BALB/c, but not in C57BL/6J mice (Adami et al ., ).…”

“…However, the findings are not fully consistent as the H 4 receptor agonists VUF8430 and VUF10460 had no effect on indomethacin/bethanecol‐induced lesions in a mouse model whereas the HCl‐induced damage in rats was enhanced by both agonists, and in contrast, indomethacin‐induced ulcerations were reduced by VUF10460 (Coruzzi et al ., 2009; 2011; Adami et al ., ). It was hypothesized that species and strain differences might contribute to the differential effects as JNJ7777120 effectively reduced indomethacin/bethanecol‐induced lesions in CD‐1, NMRI and BALB/c, but not in C57BL/6J mice (Adami et al ., ). However, it should be kept in mind that several of the compounds used also display considerable affinity for the H 3 receptor, such as VUF8430 [pK i for rat H 4 receptors of 6.9 vs. 6.5 for rat H 3 receptors (Lim et al ., ); Table ], again underscoring the need for selective H 4 receptor ligands.…”

“…Overall, the data gathered to date suggest that H 4 receptors do not participate in gastric acid secretion under physiological conditions as neither H 4 receptor agonists such as VUF8430 and VUF10460 nor H 4 receptor antagonists such as JNJ7777120 and VUF5949 affected basal acid production or the macroscopic appearance of the stomach (Lim et al ., ; Coruzzi et al ., ; Adami et al ., ). However, when the mucosal integrity was compromised such as in models of chemically induced gastric ulceration, damage was significantly enhanced by H 4 receptor stimulation and markedly reduced by its blockade (Adami et al ., 2005; 2012; Coruzzi et al ., 2009; 2011). In addition, enhanced chemically induced mucosal damage by H 4 receptor agonists could be prevented by concomitant H 4 receptor antagonists and vice versa (Coruzzi et al ., 2009; 2011).…”

Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity

“…Low to high doses of JNJ7777120 were used in our set-up, ranging from 10 up to 140 mg/kg, based on the compound's pharmacokinetic profile, previous reports in the literature and the high affinity of histamine for the H4R compared with the H1R 19 21. JNJ7777120 currently serves as the reference compound for H4R antagonists due to its high affinity for the H4R, which is in the nanomolar range (K i =4.2 nM for rat H4R) 16 21.…”

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

“…In rodents the reference H 4 R 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 H 4 R blockade was unrelated to antisecretory effects or alteration in GI motility; 35 moreover, it was found to differ from that induced by activation of H 3 Rs, since it was not evidenced against necrotizing agents, such as concentrated acid.…”