The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice.
BACKGROUND
Although histamine H1 receptor (H1R) antagonists are commonly used to treat atopic dermatitis, the treatment is not always effective. The histamine H4 receptor (H4R) was recently described as important to the pruritus in dermatitis. Here, we investigated whether the combination of a H1R antagonist plus a H4R antagonist attenuates chronic dermatitis in NC/Nga mice.


METHODS
Chronic dermatitis was developed by repeated challenges with picryl chloride on the dorsal back and ear lobes. The therapeutic effects of the H1R antagonist olopatadine and H4R antagonist JNJ7777120 on scratching and the severity of dermatitis were evaluated. In addition, the mechanisms responsible for the anti-allergic effects of H1R and/or H4R antagonism were examined using bone marrow-derived mast cells (BMMC) and keratinocytes.


RESULTS
JNJ7777120 attenuated scratching behavior after a single administration and improved dermatitis, as assessed with clinical scores, pathology, and cytokine levels in skin lesions when administered repeatedly. These effects were augmented by combined treatment with olopatadine, having a similar therapeutic efficacy to prednisolone. JNJ7777120 inhibited dose-dependently the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 from antigen-stimulated BMMC. In addition, olopatadine reversed the histamine-induced reduction of semaphorin 3A mRNA in keratinocytes.


CONCLUSIONS
Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. yuusuke_oosawa@pharm.kissei.co.jp
Y
Y
Ohsawa
N
N
Hirasawa
D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D054414:Chemokine CCL17 / Q000096:biosynthesis; D054422:Chemokine CCL22 / Q000096:biosynthesis; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D003990:Dibenzoxepins / Q000008:administration & dosage; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006632:Histamine / Q000276:immunology / Q000494:pharmacology; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D006636:Histamine Release / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000069605:Olopatadine Hydrochloride; D010853:Picryl Chloride / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage; D011969:Receptors, Histamine H1 / Q000276:immunology; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism
D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D016207:Cytokines; D003990:Dibenzoxepins; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D007211:Indoles; D010879:Piperazines; D011969:Receptors, Histamine H1; D040121:Semaphorin-3A; D000069605:Olopatadine Hydrochloride; D007073:Immunoglobulin E; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D006632:Histamine; D010853:Picryl Chloride