title: Safer topical treatment for inflammation using 5α-tetrahydrocorticosterone in mouse models.
abstract: Use of topical glucocorticoid for inflammatory skin conditions is limited by systemic and local side-effects. This investigation addressed the hypothesis that topical 5α-tetrahydrocorticosterone (5αTHB, a corticosterone metabolite) inhibits dermal inflammation without affecting processes responsible for skin thinning and impaired wound healing. The topical anti-inflammatory properties of 5αTHB were compared with those of corticosterone in C57Bl/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. 5αTHB decreased dermal swelling and total cell infiltration associated with dermatitis similarly to corticosterone after 24h, although at a five fold higher dose, but in contrast did not have any effects after 6h. Pre-treatment with the glucocorticoid receptor antagonist RU486 attenuated the effect of corticosterone on swelling at 24h, but not that of 5αTHB. After 24h 5αTHB reduced myeloperoxidase activity (representative of neutrophil infiltration) to a greater extent than corticosterone. At equipotent anti-inflammatory doses 5αTHB suppressed angiogenesis to a limited extent, unlike corticosterone which substantially decreased angiogenesis compared to vehicle. Furthermore, 5αTHB 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 5αTHB, reduced collagen deposition. However, both 5αTHB and corticosterone attenuated macrophage infiltration into sponges. In conclusion, 5αTHB 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.
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: A.Gastaldello@soton.ac.uk.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Gastaldello
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom; Centre for Integrative Physiology, Hugh Robson Building, University of Edinburgh, 15 George Square, Edinburgh EH8 9XD, United Kingdom. Electronic address: Dawn.Livingstone@ed.ac.uk.
authors.forename: Dawn E W
authors.initials: DE
authors.lastname: Livingstone
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: s1358252@sms.ed.ac.uk.
authors.forename: Amber J
authors.initials: AJ
authors.lastname: Abernethie
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: nhyt3@cam.ac.uk.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tsang
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: B.Walker@ed.ac.uk.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: Patrick.Hadoke@ed.ac.uk.
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.affiliation: University/British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: Ruth.Andrew@ed.ac.uk.
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
mesh_terms: D000287:Administration, Topical; D000818:Animals; D003345:Corticosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C003676:tetrahydrocorticosterone; D003345:Corticosterone
keywords: 5α-Tetrahydrocorticosterone; 5α-Tetrahydrocorticosterone (PubChem CID: 101790); Angiogenesis; Collagen; Corticosterone (PubChem CID: 5753); Dermatitis; Glucocorticoid; Mifepristone (PubChem CID: 55245); Wound healing