Binding of the anti-inflammatory steroid deflazacort to glucocorticoid receptors in brain and peripheral tissues. In vivo and in vitro studies.
Deflazacort (DFC) is a heterocyclic glucocorticoid with anti-inflammatory activity but with decreased side effects. In this study, we have evaluated the capacity of DFC and other glucocorticoids to reach the central nervous system (CNS) in vivo by measuring changes of [3H]dexamethasone (DEX) binding to glucocorticoid receptors (GR) in vitro. GR occupation was effected by DEX in the cerebral cortex, hippocampus, pituitary, liver and thymus, with DFC showing a similar profile except for the cerebral cortex. In contrast, corticosterone weakly occupied GR in the thymus, pituitary and hippocampus and methyl-prednisolone was active only in peripheral tissues. Furthermore, IC50 for DEX in vitro amounted to 15-17 nM in the hippocampus and liver, whereas IC50 for the active metabolite 21-deacetyl-DFC (21-OH-DFC) was 4 times higher. 21-OH-DFC bound to type II and was absent from type I GR. When tested in equipotent doses based on IC50 analysis, DFC and DEX similarly induced in vivo ornithine decarboxylase activity in hippocampus and liver, although body weight loss after chronic treatment was significantly less for DFC. The results show that DFC distributes on the CNS similarly to DEX, induces ornithine decarboxylase activity but presents less intensive catabolic effects, making it suitable for use as an anti-inflammatory steroid during chronic therapeutic regimes.
Coirini
H
H
Laboratorio de Bioquimica Neuroendocrina, Instituto de Biologia y Medicina Experimental, Obligado, Argentina.
Flores
D
D
Vega
M C
MC
Gonzalez Deniselle
M C
MC
De Nicola
A F
AF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000378:metabolism / Q000493:pharmacokinetics; D006624:Hippocampus / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008775:Methylprednisolone / Q000378:metabolism / Q000493:pharmacokinetics; D009929:Organ Size / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D011241:Prednisone / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D011282:Pregnenediones / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D011282:Pregnenediones; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D009955:Ornithine Decarboxylase; C021988:deflazacort; D011241:Prednisone; D003345:Corticosterone; D008775:Methylprednisolone