Glucocorticoids are the standard of care for many inflammatory conditions, including lupus, asthma, rheumatoid arthritis, and muscular dystrophy. However, the side-effect profiles of pharmacological glucocorticoids are significant, including muscle atrophy, osteoporosis, spleen atrophy, and mood and sleep disorders. This has led to a search for dissociative steroids—drugs able to retain efficacy without the side effects. This study investigated a glucocorticoid derivative with Δ-9,11 modifications as a dissociative steroid. The Δ-9,11 analog showed potent inhibition of tumor necrosis factor (TNF) α-induced nuclear factor-κB (NF-κB) signaling in cell reporter assays, and this transrepression activity was blocked by mifepristone (RU486), showing the requirement for the glucocorticoid receptor (GR). The Δ-9,11 analog induced nuclear translocation of GR but showed loss of transactivation as assayed by GR-luciferase constructs, as well as mRNA profiles of treated cells. The Δ-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy. Daily oral delivery of Δ-9,11 analog showed reduction of muscle inflammation and improvements in multiple muscle function assays, yet no reductions in body weight or spleen size, suggesting loss of key side effects. The data demonstrate that a Δ-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities.
See article at J Pharmacol Exp Ther 2012, 343:225–232.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics