Unit of Neuroscience, Department of Medicine and Surgery, University of Parma, 43125, Parma, Italy.
Unit of Biomedical, Biotechnological and Translational Sciences, Department of Medicine and Surgery, University of Parma, 43125, Parma, Italy.
Naunyn Schmiedebergs Arch Pharmacol. 2018 Dec;391(12):1387-1397. doi: 10.1007/s00210-018-1553-x. Epub 2018 Aug 25.
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.
组胺 H4 受体（H4R）拮抗剂的抗炎作用为炎症/过敏疾病的治疗开辟了新的治疗选择，但 H4R 在炎症中的作用还远未解决。本研究旨在研究结构相关的氨基嘧啶类 H4R 配体（具有不同效能和功能的中性拮抗剂 ST-994、部分激动剂 ST-1006、反向激动剂 ST-1012 和部分反向激动剂 ST-1124）在小鼠巴豆油耳肿胀和瘙痒中的作用。在巴豆油局部应用前，皮下给予 H4R 配体。虽然 ST-1006 和 ST-1124 在任何测试剂量（10-100mg/kg）下均无效，但 ST-994 和 ST-1012（30 和 100mg/kg）均显著减轻了巴豆油引起的耳肿胀。此外，ST-994、ST-1006 和 ST-1124 但不是 ST-1012，在 30mg/kg 时显著抑制了巴豆油引起的耳瘙痒。与参考 H4R 拮抗剂 JNJ7777120（100mg/kg）的结果一致，对炎症耳组织的组织学检查表明，用 ST-994（30mg/kg）治疗导致炎症严重程度评分显著降低，浸润组织的嗜酸性粒细胞数量减少，而与完整肥大细胞数量相比，炎症组织中脱颗粒肥大细胞的数量增加。这些数据表明，巴豆油诱导的耳炎症和瘙痒似乎明显但不同地受到测试的 H4R 配体的影响。H4R 中性拮抗剂 ST-994 的双重作用的潜在优势需要仔细考虑，作为治疗炎症性疾病的新治疗方法。
