Background: The 5α-reduced glucocorticoid, 5α-tetrahydrocorticosterone (5α-THB), displays a dissociated steroid profile exhibiting anti-inflammatory effects in a murine model of thioglycollate-induced peritonitis but failing to induce adverse metabolic effects caused by corticosterone. We assessed the topical anti-inflammatory properties of 5α-THB in a model of irritant dermatitis. Given the adverse effects of steroids on cutaneous wound healing, we also investigated the anti-angiogenic properties of 5α-THB in vivo.
Methods: Ears of mice (n=10/group) were topically treated with irritant croton oil (CO, 300 μg) alone or with corticosterone (applied at EC50 dose, 5 μg) or 5α-THB (5, 15, and 25 μg) for 24 h. Swelling was assessed by ear weight at cull. To study angiogenesis, polyurethane sponges containing either 5α-THB (3 and 15 mg), corticosterone (3 mg), or vehicle, were implanted subcutaneously in mice (812/group) for 21 days. Newly formed vessels were analysed histologically; endothelial and smooth muscle cells and infiltrating macrophages were investigated immunohistochemically (CD31, αSMA, F4/80), and transcript profiles by qPCR. Data are mean±S.E.M., CO/vehicle group set to 100%, *P<0.05.
Results: 5α-THB decreased swelling similarly to corticosterone, but required a higher dose (25 μg 5α-THB, swelling reduced to 65±8%* vs 5 μg corticosterone, to 57±4%*). Corticosterone decreased the number of new vessels to 15±3%* whereas 5α-THB had less effect even at higher dose (3 mg, 87±13% NS; 15 mg, 46±7%*). While corticosterone inhibited both endothelial and smooth muscle cell recruitment (to 2±0.7 and 12±3%* respectively) and decreased transcripts of genes involved in angiogenesis and inflammation, 5α-THB inhibited only endothelial cell recruitment at high dose (15 mg, reduced to 20±5%*), without affecting the same transcripts. 5α-THB and corticosterone both attenuated the number of macrophages infiltrating the sponges (3 and 15 mg 5α-THB to 48±4% NS and 49±2*; corticosterone to 39±3%*). Importantly for repercussion on wound healing and skin homeostasis, 5α-THB unlike corticosterone did not decrease amount of collagen in sponges (3 and 15mg 5α-THB, changed to 106±16% NS and 128±20% NS vs corticosterone, 30±8%*).
Conclusions: 5α-THB displays the profile of a safer anti-inflammatory compound for topical application with limited effects on angiogenesis and extracellular matrix indicating it is less likely to impair wound healing or cause skin thinning.
02 Nov 2015 - 04 Nov 2015