Abstract
The anti-inflammatory effects of histamine H4 receptor (H4R) antagonists opened new therapeutic options for the treatment of inflammatory/allergic diseases, but the role of H4R in inflammation is far from being solved. Aim of the present study was to investigate the role of structurally related H4R ligands of the aminopyrimidine class with different efficacies and functionalities (neutral antagonist ST-994, partial agonist ST-1006, inverse agonist ST-1012, and partial inverse agonist ST-1124) on croton oil-induced ear edema and pruritus in mice. The H4R ligands were administered subcutaneously before topical application of croton oil. While ST-1006 and ST-1124 were ineffective at any dose tested (10–100 mg/kg), both ST-994 and ST-1012 (30 and 100 mg/kg) significantly reduced croton oil-induced ear edema. Moreover, ST-994, ST-1006, and ST-1124, but not ST-1012, significantly inhibited croton oil-induced ear pruritus at 30 mg/kg. In accordance with results obtained with the reference H4R antagonist JNJ7777120 (100 mg/kg), histological examination of inflamed ear tissue indicated that treatment with ST-994 (30 mg/kg) led to a significant reduction in the inflammatory severity score and in the number of eosinophils infiltrating the tissue, while the number of degranulated mast cells in inflamed tissues was increased in comparison with the number of intact mast cells. These data indicate that croton oil-induced ear inflammation and pruritus seem to be clearly, but variably, affected by the H4R ligands tested. The potential advantage of dual effect of the H4R neutral antagonist ST-994 has to be carefully considered as a new therapeutic approach to the treatment of inflammatory diseases.
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Acknowledgments
The authors are grateful to Marco Gazza for skillful technical assistance.
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This work was kindly supported by a grant from the University of Parma (FIL 2014, D.R. 674), the DFG INST-208/664-1, and the COST Action CA15135.
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M.A. designed the research study, carried out the experimental pharmacological work, analyzed data, and wrote the manuscript; D.G. and C.M. performed the histological study, analyzed data, and contributed to the manuscript preparation; H.S. synthesized the H4R ligands, contributed to data discussion, and manuscript preparation.
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All applicable international, national, and institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors. The experimental protocol was carried out after approval by the Animal Care and Research Ethics Committee of the University of Parma (Italy), under license from the Italian Department of Health (authorization n° 38/2016-PR). All studies involving animals are reported in accordance with the ARRIVE guidelines for reporting experiments involving animals (Kilkenny et al. 2010; McGrath et al. 2010).
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Maristella Adami and Cristina Micheloni should have been listed as first co-authors.
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Adami, M., Micheloni, C., Grandi, D. et al. Differential effects of functionally different histamine H4 receptor ligands on acute irritant dermatitis in mice. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1387–1397 (2018). https://doi.org/10.1007/s00210-018-1553-x
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DOI: https://doi.org/10.1007/s00210-018-1553-x