ABSTRACT
Title
Gastroprotective effect of the histamine H4 receptor antagonist JNJ7777120 in mice
Authors
M. Adami1, C. Pozzoli1, R. Smits2, R. Leurs2, A. Menozzi3, S. Bertini3, B. Passeri3, A.M. Cantoni3, G. Coruzzi1
1Dept. of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Italy; 2LACDR, Dept. of Medicinal Chemistry, Vrije Universiteit Amsterdam, The Netherlands; 3Dept. of Animal Health, University of Parma, Italy
1Dept. of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Italy; 2LACDR, Dept. of Medicinal Chemistry, Vrije Universiteit Amsterdam, The Netherlands; 3Dept. of Animal Health, University of Parma, Italy
Abstract
Immunohistochemical studies have detected histamine H4 receptors (H4Rs) in the gastrointestinal tract of both rodents and humans; in particular, H4R expression was found in mast cells, neurons and ghrelin-producing cells (Coruzzi et al., 2011). Based on the protective effect exerted by the H4R antagonist JNJ7777120 against the gastric lesions induced by indomethacin in rats (Adami et al., 2005) and the existence of large species variations in the pharmacological profiles of H4Rs previously highlighted by Liu et al. (2001), in the present studywe examined whether H4Rs have a role in mouse gastric mucosal defence. We tested the H4R antagonist JNJ7777120 and the H4R agonists VUF10460 and VUF8430, which in binding experiments displayed high affinity at human H4Rs (Smits et al., 2009). The selective H4R ligands were synthesized by one of us (RS).
The effects of selective H4R ligands were investigated in fasted CD1 mice against the ulcerogenic effect induced by concomitant administration of indomethacin (IND, 30 mg/kg sc) + bethanechol (BET, 5 mg/kg ip) (Rainsford KD, 1987). The development of gastric lesions was assessed 4 h after the administration of the compounds. “Lesion index” was determined by measuring each hemorrhagic lesion along its greatest length (mm). In separate experiments, the histological tissue damage was investigated at 4 h after IND+BET administrations alone or in the presence of sc injection of different H4R ligands.
JNJ7777120, VUF10460 and VUF8430 did not damage to the stomach at any dose tested (3-30 mg/kg sc), whereas IND+BET provoked gross hemorrhagic lesions in the gastric mucosa (lesion index: 43.56±6.28 mm, n= 18). JNJ7777120 (3-30 mg/kg sc) significantly reduced the gastric lesions induced by concomitant administration of IND+BET(lesion index: 12.57±3.99 mm, n= 7, and lesion index: 19.56±4.73 mm, n= 9, for JNJ7777120 at 10 and 30 mg/kg sc, respectively, P<0.01), while both VUF10460 and VUF8430 were ineffective. The gastroprotection induced by JNJ7777120 (10 mg/kg sc) was prevented by prior administration of the H4R agonist VUF8430 (30 mg/kg sc).
In conclusion, data obtained with selective ligands are in line with our previous data in rats and confirm a role of H4Rs in gastric ulcerogenesis.
Adami et al. (2005). 34th Meeting of the EHRS, Bled, Slovenia, May 11-14, p. 47
Coruzzi et al. (2011). Front Biosci. Special Issue (in press).
Rainsford KD (1987). J Pharm Pharmacol. 39, 669-672
Smits et al. (2009). Drug Discov Today.14, 745-753
Liu, et al. (2001). J Pharmacol Exp Ther. 299, 121-130
The Authors acknowledge support from the EU-KP7 COST programme BM0806 (Histamine H4receptor network).
The effects of selective H4R ligands were investigated in fasted CD1 mice against the ulcerogenic effect induced by concomitant administration of indomethacin (IND, 30 mg/kg sc) + bethanechol (BET, 5 mg/kg ip) (Rainsford KD, 1987). The development of gastric lesions was assessed 4 h after the administration of the compounds. “Lesion index” was determined by measuring each hemorrhagic lesion along its greatest length (mm). In separate experiments, the histological tissue damage was investigated at 4 h after IND+BET administrations alone or in the presence of sc injection of different H4R ligands.
JNJ7777120, VUF10460 and VUF8430 did not damage to the stomach at any dose tested (3-30 mg/kg sc), whereas IND+BET provoked gross hemorrhagic lesions in the gastric mucosa (lesion index: 43.56±6.28 mm, n= 18). JNJ7777120 (3-30 mg/kg sc) significantly reduced the gastric lesions induced by concomitant administration of IND+BET(lesion index: 12.57±3.99 mm, n= 7, and lesion index: 19.56±4.73 mm, n= 9, for JNJ7777120 at 10 and 30 mg/kg sc, respectively, P<0.01), while both VUF10460 and VUF8430 were ineffective. The gastroprotection induced by JNJ7777120 (10 mg/kg sc) was prevented by prior administration of the H4R agonist VUF8430 (30 mg/kg sc).
In conclusion, data obtained with selective ligands are in line with our previous data in rats and confirm a role of H4Rs in gastric ulcerogenesis.
Adami et al. (2005). 34th Meeting of the EHRS, Bled, Slovenia, May 11-14, p. 47
Coruzzi et al. (2011). Front Biosci. Special Issue (in press).
Rainsford KD (1987). J Pharm Pharmacol. 39, 669-672
Smits et al. (2009). Drug Discov Today.14, 745-753
Liu, et al. (2001). J Pharmacol Exp Ther. 299, 121-130
The Authors acknowledge support from the EU-KP7 COST programme BM0806 (Histamine H4receptor network).