The glucocorticoid receptor agonistic modulators CpdX and CpdX-D3 do not generate the debilitating effects of synthetic glucocorticoids
| Autor: | Laetitia Paulen, Pierre Chambon, Guoqiang Hua, Naimah Zein |
|---|---|
| Přispěvatelé: | univOAK, Archive ouverte, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
Mice Transactivation Receptors Glucocorticoid Glucocorticoid receptor medicine Adrenal insufficiency Animals Humans Colitis Receptor Glucocorticoids Transrepression Inflammation Multidisciplinary business.industry Fatty liver [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences medicine.disease [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences Fatty Liver Diabetes Mellitus Type 2 PNAS Plus Osteoporosis Steroids business Glucocorticoid medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (28), pp.14200-14209. ⟨10.1073/pnas.1908264116⟩ |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1908264116 |
| Popis: | Seventy years after the discovery of their anti-inflammatory properties, glucocorticoids (GCs) remain the mainstay treatment for major allergic and inflammatory disorders, such as atopic dermatitis, asthma, rheumatoid arthritis, colitis, and conjunctivitis, among others. However, their long-term therapeutical administration is limited by major debilitating side effects, e.g., skin atrophy, osteoporosis, Addison-like adrenal insufficiency, fatty liver, and type 2 diabetes syndrome, as well as growth inhibition in children. These undesirable side effects are mostly related to GC-induced activation of both the direct transactivation and the direct transrepression functions of the GC receptor (GR), whereas the activation of its GC-induced indirect tethered transrepression function results in beneficial anti-inflammatory effects. We have reported in the accompanying paper that the nonsteroidal compound CpdX as well as its deuterated form CpdX-D3 selectively activate the GR indirect transrepression function and are as effective as synthetic GCs at repressing inflammations generated in several mouse models of major pathologies. We now demonstrate that these CpdX compounds are bona fide selective GC receptor agonistic modulators (SEGRAMs) as none of the known GC-induced debilitating side effects were observed in the mouse upon 3-mo CpdX treatments. We notably report that, unlike that of GCs, the administration of CpdX to ovariectomized (OVX) mice does not induce a fatty liver nor type 2 diabetes, which indicates that CpdX could be used in postmenopausal women as an efficient "harmless" GC substitute. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|