Effects of histamine H4 receptor ligands in a mouse model of gastric ulceration

Pharmacology. 2012;89(5-6):287-94. doi: 10.1159/000337736.


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 antagonist 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 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 H(4)R 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 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 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 potential advantage of H(4)R 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 H(4)R functions and/or new selective ligands.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Bethanechol
  • Disease Models, Animal
  • Guanidines / therapeutic use
  • Histamine Agonists / therapeutic use*
  • Histamine Antagonists / therapeutic use*
  • Indoles / therapeutic use
  • Indomethacin
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Piperazines / therapeutic use
  • Pyrimidines / therapeutic use
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Histamine / metabolism
  • Receptors, Histamine H4
  • Species Specificity
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / drug therapy*
  • Stomach Ulcer / pathology
  • Thiourea / analogs & derivatives
  • Thiourea / therapeutic use


  • Anti-Inflammatory Agents
  • Guanidines
  • Histamine Agonists
  • Histamine Antagonists
  • Hrh4 protein, mouse
  • Indoles
  • Piperazines
  • Pyrimidines
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • S-(2-guanidylethyl)isothiourea
  • Bethanechol
  • 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
  • Thiourea
  • Indomethacin