University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, UK.
Br J Pharmacol. 2024 Apr;181(8):1256-1267. doi: 10.1111/bph.16285. Epub 2023 Dec 28.
Glucocorticoids are powerful anti-inflammatory drugs, but are associated with many side-effects. Topical application in atopic dermatitis leads to skin thinning, metabolic changes, and adrenal suppression. 5α-Tetrahydrocorticosterone (5αTHB) is a potential selective anti-inflammatory with reduced metabolic effects. Here, the efficacy and side-effect profile of 5αTHB were compared with hydrocortisone in preclinical models of irritant dermatitis.
Acute irritant dermatitis was invoked in ear skin of male C57BL/6 mice with a single topical application of croton oil. Inflammation was assessed as oedema via ear weight following treatment with 5αTHB and hydrocortisone. Side-effects of 5αTHB and hydrocortisone were assessed following chronic topical steroid treatment (28 days) to non-irritated skin. Skin thinning was quantified longitudinally by caliper measurements and summarily by qPCR for transcripts for genes involved in extracellular matrix homeostasis; systemic effects of topical steroid administration also were assessed. Clearance of 5αTHB and hydrocortisone were measured following intravenous and oral administration.
5αTHB suppressed ear swelling in mice, with ED similar to hydrocortisone (23 μg vs. 13 μg). Chronic application of 5αTHB did not cause skin thinning, adrenal atrophy, weight loss, thymic involution, or raised insulin levels, all of which were observed with topical hydrocortisone. Transcripts for genes involved in collagen synthesis and stability were adversely affected by all doses of hydrocortisone, but only by the highest dose of 5αTHB (8× ED ). 5αTHB was rapidly cleared from the systemic circulation.
Topical 5αTHB has potential to treat inflammatory skin conditions, particularly in areas of delicate skin.
糖皮质激素是一种强大的抗炎药物，但也有许多副作用。在特应性皮炎中局部应用会导致皮肤变薄、代谢改变和肾上腺抑制。5α-四氢皮质酮（5αTHB）是一种潜在的选择性抗炎药，代谢作用降低。在这里，5αTHB 的疗效和副作用与氢化可的松在刺激性皮炎的临床前模型中进行了比较。
雄性 C57BL/6 小鼠耳皮单次涂抹巴豆油诱发急性刺激性皮炎。用 5αTHB 和氢化可的松治疗后，通过耳重评估水肿作为炎症。在非刺激性皮肤进行慢性局部皮质类固醇治疗（28 天）后，评估 5αTHB 和氢化可的松的副作用。通过卡尺测量和涉及细胞外基质稳态的基因转录物的 qPCR 进行皮肤变薄的纵向量化；还评估了局部类固醇给药的全身作用。静脉和口服给药后测量 5αTHB 和氢化可的松的清除率。
5αTHB 抑制了小鼠的耳肿胀，其 ED 与氢化可的松相似（23μg 对 13μg）。慢性应用 5αTHB 不会导致皮肤变薄、肾上腺萎缩、体重减轻、胸腺萎缩或胰岛素水平升高，这些都是局部应用氢化可的松观察到的。所有剂量的氢化可的松都对涉及胶原蛋白合成和稳定性的基因转录物产生不利影响，但只有最高剂量的 5αTHB（8×ED）会产生影响。5αTHB 从全身循环中迅速清除。
局部应用 5αTHB 有可能治疗炎症性皮肤病，特别是在皮肤娇嫩的部位。
