Endocrine Abstracts (2009) 20 S28.2

Glucocorticoid receptor ligands, dissociating between transrepression and transactivation

Guy Haegeman

LEGEST-University Gent, Gent, Belgium.

Glucocorticoid hormones (GCs) remain the mainstay for the treatment of various inflammatory disorders, because of their great efficacy. The long-term usage of GCs is, however, overshadowed by the occurrence of debilitating side-effects, like osteoporosis, skin and muscle atrophy, diabetes and neurological disorders. GCs exert their functions through binding to the glucocorticoid receptor (GR), a transcription factor that regulates gene transcription in a positive or negative way. Direct binding of activated GR in the promoter of target genes is believed to be the main pathway leading to metabolic gene expression (mainly hold responsible for the unwanted side-effects), whereas the interference of GR with the activity of other transcription factors, such as NF-κB or AP-1, greatly contributes to its desired anti-inflammatory capacities. ‘Dissociated ligands’ thus aim to separate GR-mediated transcriptional activation from transcriptional repression in order to achieve better side-effect profiles.

In this respect, a newly characterized, plant-derived, non-steroidal GR modulator, i.e. Compound A (CpdA) was tested both in vitro and in vivo for its dissociative effects.

Methodology: We have used CpdA in several cellular in vitro assays as well as in in vivo disease models to test its dissociated properties, as compared to glucocorticoids.

Results: CpdA behaves as a potent (although weaker) anti-inflammatory agent, both in vitro as in vivo, as compared to the synthetic glucocorticoid Dexamethasone. However, as opposed to steroidal ligands, CpdA does not give rise to the gene-activating effects in cells, nor to increased blood glucose levels or hyperinsulinemia in the tested animals. Furthermore, as opposed to glucocorticoids, CpdA does not lead to GR desensitization.

Conclusions: It is possible to fully dissociate the gene-activating effects from the inhibitory actions of GR by imposing a monomeric structure to the receptor by so-called ‘specific GR modulators’ (SGRMs), like CpdA. Moreover, GR desensitization can be avoided which adds to the beneficial effects for long-term treatments.

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