title: Effects of histamine H4 receptor ligands in a mouse model of gastric ulceration.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Parma, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Adami
authors.forename: Cristina
authors.initials: C
authors.lastname: Pozzoli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Menozzi
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Benedetta
authors.initials: B
authors.lastname: Passeri
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cantoni
authors.forename: Rogier
authors.initials: R
authors.lastname: Smits
authors.forename: Iwan
authors.initials: I
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coruzzi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D018723:Bethanechol; D004195:Disease Models, Animal; D006146:Guanidines / Q000627:therapeutic use; D017442:Histamine Agonists / Q000627:therapeutic use*; D006633:Histamine Antagonists / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use; D007213:Indomethacin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013045:Species Specificity; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D006146:Guanidines; D017442:Histamine Agonists; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C516215:S-(2-guanidylethyl)isothiourea; D018723:Bethanechol; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D013890:Thiourea; D007213:Indomethacin