Dataset Information

?-9,11 modification of glucocorticoids dissociates nuclear factor-?B inhibitory efficacy from glucocorticoid response element-associated side effects.

ABSTRACT: Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-?B (NF-?B) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a ?-9,11 modification as a dissociative steroid. The ?-9,11 analog showed potent inhibition of tumor necrosis factor-?-induced NF-?B signaling in cell reporter assays, and this transrepression activity was blocked by 17?-hydroxy-11?-[4-dimethylamino phenyl]-17?-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The ?-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The ?-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the ?-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a ?-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, ?-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.

SUBMITTER: Baudy AR

PROVIDER: S-EPMC3464029 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Δ-9,11 modification of glucocorticoids dissociates nuclear factor-κB inhibitory efficacy from glucocorticoid response element-associated side effects.

Baudy Andreas R AR Reeves Erica K M EK Damsker Jesse M JM Heier Christopher C Garvin Lindsay M LM Dillingham Blythe C BC McCall John J Rayavarapu Sree S Wang Zuyi Z Vandermeulen Jack H JH Sali Arpana A Jahnke Vanessa V Duguez Stephanie S DuBois Debra D Rose Mary C MC Nagaraju Kanneboyina K Hoffman Eric P EP

The Journal of pharmacology and experimental therapeutics 20120628 1

Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-κB (NF-κB) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated ...[more]

PMID: 22743576

Similar Datasets

Project description:BackgroundGlucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes.MethodsWe used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA.ResultsIn mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy.ConclusionsOverall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.

Dataset Information

?-9,11 modification of glucocorticoids dissociates nuclear factor-?B inhibitory efficacy from glucocorticoid response element-associated side effects.

Publications

Δ-9,11 modification of glucocorticoids dissociates nuclear factor-κB inhibitory efficacy from glucocorticoid response element-associated side effects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets