Effects of the H4 receptor antagonist JNJ7777120 in mice: focus on strain-related differenes

The histamine H4 receptor (H4R)has been identified in immune/inflammatory cells of different species and has been proposed as a new target for anti-inflammatory/antiallergic drugs (Smits et al., 2009). In the present study, the effect of the selective H4R antagonist JNJ7777120 was investigated in different experimental models from the mouse, focusing on possible strain-related differences. The anti-inflammatory activity of JNJ7777120 was tested, in comparison with dexamethasone, in the ear edema assay by application of 2.5% croton oil (CO). Ear weight and histological tissue damage were investigated at different times (2-4 h) after CO administration. Gastric lesions were evaluated in fasted mice, 4 h after indomethacin (30 mg/kg sc) + bethanechol (5 mg/kg ip) (Rainsford KD, 1987). JNJ7777120 (30-100 mg/kg sc) significantly reduced both ear weight and histological damage at 2 h (maximum inhibition 40-50%, n=6-8), but not at 4 h (n=8). This effect was observed in CD1, but not in C57BL/6J or NMRI mice. Moreover, in CD1 and NMRI strains, but not in the C57BL/6J, dexamethasone (2 mg/kg sc) displayed anti-inflammatory effects (65% inhibition on ear weight, n=6-9) at any time point considered. JNJ7777120 (3-30 mg/kg sc) did not damage the gastric mucosa and, actually, reduced the gastric lesions induced by concomitant administration of indomethacin (30 mg/kg sc) + bethanechol (5 mg/kg ip) (maximum inhibition 50% at 10 mg/kg sc, n=8). The gastroprotective effect was observed in CD1, NMRI and BALBc, but not in C57BL/6J mice. In conclusion,present data evidence the anti-inflammatory activity of JNJ7777120 in a mouse model of skin inflammation developing at 2 h, whereas the inflammatory response at 4 h was not affected. The effect of JNJ7777120 was associated to protective effects in the gastric mucosa, suggesting a new treatment of inflammation combined with gastric safety. The different effects of the H4R antagonist in various mouse strains have to be carefully considered in the pharmacological characterization of H4R functions and evaluation of new H4R ligands. Rainsford KD (1987). J. Pharm. Pharmacol. 39, 669-672 Smits et al. (2009). Drug Discov Today.14, 745-753 The Authors acknowledge support from the EU-KP7 COST programme BM0806 (Histamine H4receptor network).