jnj-7777120 and Edema

The role of histamine H(4) receptor (H(4)R) was investigated in a T-helper type 2 (Th2)-cell-mediated mouse skin inflammation model that mimics several of the features of atopic dermatitis. Treatment with two specific H(4)R antagonists before challenge with FITC led to a significant reduction in ear edema, inflammation, mast cell, and eosinophil infiltration. This was accompanied by a reduction in the levels of several cytokines and chemokines in the ear tissue. Upon ex vivo antigen stimulation of lymph nodes, H(4)R antagonism reduced lymphocyte proliferation and IL-4, IL-5, and IL-17 levels. One explanation for this finding is that lymph nodes from animals dosed with the H(4)R antagonist, JNJ 7777120, contained a lower number of FITC-positive dendritic cells. The effect of H(4)R antagonism on dendritic cell migration in vivo may be an indirect result of the reduction in tissue cytokines and chemokines or a direct effect on chemotaxis. In addition to anti-inflammatory effects, JNJ 7777120 also significantly inhibited the pruritus shown in the model. Therefore, the dual effects of H(4)R antagonists on pruritus and Th2-cell-mediated inflammation point to their therapeutic potential for the treatment of Th2-mediated skin disorders, including atopic dermatitis.

Topics: Animals; Chemotaxis; Dendritic Cells; Dermatitis, Atopic; Disease Models, Animal; Edema; Eosinophils; Fluorescein-5-isothiocyanate; Histamine Antagonists; Indoles; Interleukin-17; Interleukin-4; Interleukin-5; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Th2 Cells

Histamine is a potent mediator of itch in humans, yet histamine H(1) receptor antagonists have been shown to be of limited use in the treatment of certain chronic pruritic diseases. The histamine H(4) receptor is a recently described histamine receptor, expressed on hematopoietic cells, linked to the pathology of allergy and asthma.. The contribution of the novel histamine H(4) receptor to histaminergic and allergic pruritus was investigated.. Histamine and a selective histamine H(4) receptor agonist caused scratching responses in mice, which were almost completely attenuated in histamine H(4) receptor knockout mice or by pretreatment with the selective histamine H(4) receptor antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also potently inhibited with histamine H(4) receptor antagonist treatment or in histamine H(4) receptor knockout mice. In all cases, the inhibitory effect of histamine H(4) receptor antagonist was greater than those observed with histamine H(1) receptor antagonists. The histamine H(4) receptor-mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons.. These results demonstrate that the histamine H(4) receptor is involved in pruritic responses in mice to a greater extent than the histamine H(1) receptor.. Histamine H(4) receptor antagonists may have therapeutic utility for treating chronic pruritic diseases in humans where histamine H(1) receptor antagonists are not effective.

Topics: Animals; Disease Models, Animal; Edema; Female; Foot; Histamine; Histamine Agonists; Histamine Antagonists; Indoles; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Knockout; Piperazines; Pruritus; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H4

The effects of the highly selective histamine H4 receptor antagonists JNJ7777120 and VUF6002 were investigated on the carrageenan-induced inflammation and thermal hyperalgesia in rats. JNJ7777120 (10 and 30 mg/kg, s.c.) and VUF6002 (10 mg/kg, s.c.) significantly reduced paw edema and hyperalgesia provoked by subplantar injection of carrageenan; the effect was evident against the early (2 h) phase of inflammation. An inactive analog of VUF6002, VUF6007 (10 mg/kg, s.c.) slightly aggravated paw edema, while leaving unaltered carrageenan-induced nociception. These findings indicate that histamine H4 receptors participate in the early phase of acute inflammation induced by carrageenan in rats, influencing both edema and thermal hyperalgesia.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Benzimidazoles; Carrageenan; Disease Models, Animal; Edema; Histamine Antagonists; Hot Temperature; Hyperalgesia; Indoles; Inflammation; Male; Pain Measurement; Piperazines; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Time Factors