jnj-7777120 and Colitis

Millions of people worldwide are suffering from inflammatory bowel disease (IBD), which severely affects patients' life qualities and even life expectancies. The cause of the ailment is unknown and a profound understanding of the underlying pathogenetic mechanisms is still lacking. The biogenic amine histamine is one of several inflammatory mediators, to which a pathogenetic role in IBD has been attributed. Out of the four known histamine receptors, the histamine H4 receptor (H4R) has been demonstrated to act proinflammatory in experimental models of several inflammatory diseases. In order to evaluate a potential involvement of H4R in IBD we investigated the effect of genetic or pharmacological blockade of H4R-signaling in the model of dextran sodium sulfate (DSS)-induced colitis in mice. We analysed severity and progression of clinical signs of colitis, as well as histopathologic alterations in the colons and systemic or local cytokine concentrations. Both genetic deficiency and pharmacological blockade of H4R with the selective antagonist JNJ7777120 improved clinical and histological signs of colitis and dampened the inflammatory cytokine response. Our results indicate a proinflammatory role of histamine via H4R in IBD, thus extending the current pathophysiological understanding of IBD and demonstrating the therapeutic potential of selective H4R-antagonists for patients suffering from IBD.

Topics: Animals; Colitis; Cytokines; Dextran Sulfate; Gene Expression Regulation; Indoles; Mice; Mice, Knockout; Piperazines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4

Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model.. Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay.. Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120.. H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.

Topics: Animals; Cetirizine; Colitis; Colonoscopy; Convalescence; Disease Models, Animal; Histamine; Histamine H1 Antagonists, Non-Sedating; Histamine Release; Hypersensitivity; Indoles; Intestinal Mucosa; Male; Mast Cells; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H4; Regeneration; Trinitrobenzenesulfonic Acid

The histamine H(4) receptor is a G-protein coupled receptor with little homology to the pro-inflammatory histamine H(1) receptor, expressed on cells of the immune system with hematopoietic lineage such as eosinophils and mast cells. The effects of the recently described highly selective histamine H(4) receptor antagonists JNJ 10191584 and JNJ 7777120 have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid over 3 days in the rat. Treatment with JNJ 10191584 (10-100 mg/kg p.o., b.i.d.) caused a dose-dependent reduction in macroscopic damage, inhibition of the TNBS-provoked elevation of both colonic myeloperoxidase and tumour necrosis factor-alpha (TNF-alpha), and a reduction in the histologically assessed increase in mucosal and submucosal thickness and neutrophil infiltration. JNJ 7777120 (100 mg/kg p.o., b.i.d.) likewise reduced the macroscopic injury and the increases in colonic myeloperoxidase and TNF-alpha levels. These findings indicate a pro-inflammatory role for the histamine H(4) receptor in this model and suggest a novel pharmacological approach to the treatment of colitis.

Topics: Acute Disease; Animals; Benzimidazoles; Body Weight; Colitis; Colon; Dose-Response Relationship, Drug; Indoles; Male; Organ Size; Peroxidase; Piperazines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha