Safer Topical Treatment For Inflammation Using 5 Alpha-Tetrahydrocorticosterone In Mouse Models

Use of topical glucocorticoid for inflammatory skin conditions is limited by systemic and local side effects. This investigation addressed the hypothesis that topical 5 alpha-tetrahydrocorticosterone (5 alpha THB, a corticosterone metabolite) inhibits dermal inflammation without affecting processes responsible for skin thinning and impaired wound healing. The topical anti-inflammatory properties of 5 alpha THB were compared with those of corticosterone in C57B1/6 male mice with irritant dermatitis induced by croton oil, whereas its effects on angiogenesis, inflammation, and collagen deposition were investigated by subcutaneous sponge implantation. 5 alpha THB decreased dermal swelling and total cell infiltration associated with dermatitis similarly to corticosterone after 24 h, although at a five fold higher dose, but in contrast did not have any effects after 6 h. Pre-treatment with the glucocorticoid receptor antagonist RU486 attenuated the effect of corticosterone on swelling at 24 h, but not that of 5 alpha THB. After 24 h 5 alpha THB reduced myeloperoxidase activity (representative of neutrophil infiltration) to a greater extent than corticosterone. At equipotent anti-inflammatory doses 5 alpha THB suppressed angiogenesis to a limited extent, unlike corticosterone which substantially decreased angiogenesis compared to vehicle. Furthermore, 5 alpha THB reduced only endothelial cell recruitment in sponges whereas corticosterone also inhibited smooth muscle cell recruitment and decreased transcripts of angiogenic and inflammatory genes. Strikingly, corticosterone, but not 5 alpha THB, reduced collagen deposition. However, both 5 alpha THB and corticosterone attenuated macrophage infiltration into sponges. In conclusion, 5 alpha THB displays the profile of a safer topical anti-inflammatory compound. With limited effects on angiogenesis and extracellular matrix, it is less likely to impair wound healing or cause skin thinning. (C) 2017 The Author(s). Published by Elsevier Inc.