From RU 38486 towards Dissociated Antiglucocorticoid and Antiprogesterone

Philibert, D.; Costerousse, G.; Gaillard-Moguilewsky, M.; Nédélec, L.; Nique, F.; Tournemine, C.; Teutsch, G.

doi:10.1159/000419634

Cited by 38 publications

(18 citation statements)

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“…Conjugation of mifepristone with cholic acid demonstrated some improved hepatic selectivity and was shown to reduce glucose and lipids in animal models of diabetes without activating the HPA axis (54). In other studies, optimization of the steroidal core led to the development of RU-43044 with increased selectivity to GCCR but with limited efficacy (14). In the present study, GCCR ASO treatment did not affect the expression of either GCCR or POMC genes in the pituitary gland, nor did it change plasma corticosterone and ACTH levels.…”

Section: Discussioncontrasting

confidence: 42%

Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism

et al. 2005

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Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in ϳ75 and ϳ40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by ϳ65% decrease in fed and ϳ30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and ϳ20 and 35% decrease in plasma resistin and tumor necrosis factor-␣ levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused ϳ40% decrease in fed and fasted glucose levels and ϳ50% reduction in plasma triglycerides. In ZDF and high-fat diet-fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused ϳ60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40 -70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GCresponsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasoneinduced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.

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Section: Discussioncontrasting

confidence: 42%

Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism

et al. 2005

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“…Based on these results, use of mouse uterine weight bioassay for screening and identification of antiprogestins is not recommended but it is still suitable for characterization of newly synthetized antiprogestins. Unlike MI, which in our experiments had no antiandrogenic activities measured according to seminal vesicle weights, RU displayed a full androgenic effect at a daily dose of 100 µg and 500 µg in both prepubertal and adult castrated male mice similarly as in the rat prostate (Philibert et al 1989(Philibert et al , 1991. The fact that the same molecule of antiprogestin may also exhibit antiglucocorticoid (MI), androgenic (RU; RU 49295), antiandrogenic (MI) or progestomimetic (RU 49295) effects (Philibert et al 1989(Philibert et al , 1991 may explain variable responses of uterus and seminal vesicles to ON, MI and RU in our experiments.…”

Section: Discussioncontrasting

confidence: 60%

“…The new derivative RU was about three times more active than that of MI for inducing abortion in rats and was devoid of any antiglucocorticoid activity on the thymus weight in rats. However, in contrast to MI, it has significant androgenic activity on rat prostate and also exhibits a slight progestomimetic activity on rat endometrial proliferation (Philibert et al 1989(Philibert et al , 1991Chwalisz et al 1998). ON is the 13α-methyl-substituted antiprogestin that shares a number of structural similarities to MI; ON being less antiglucocorticoid than MI.…”

Section: Discussionmentioning

confidence: 99%

Biological Responses of Antiprogestins in Mammary Gland, Uterus and Seminal Vesicles of Prepubertal Intact and Adult Gonadectomized Mice

2006

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Köhlerová E., J. Kotanová, J. ·karda: Biological Responses of Antiprogestins in Mammary Gland, Uterus and Seminal Vesicles of Prepubertal Intact and Adult Gonadectomized Mice. Acta Vet. Brno 2006, 75: 319-328.The present study tested and compared the antiproliferative and proliferative activities of three antiprogestins on four separate mouse model systems: prepubertal intact and adult ovariectomized (OVX) females, prepubertal intact and adult castrated males. In prepubertal intact males and females and adult castrated males, norethindrone acetate (NA; a synthetic steroid exhibiting progestational and estrogenic activities)-stimulated mammary growth was decreased by antiprogestins: more by RU 46556 (RU) than RU 38486 (MI) and onapristone (ON) . In adult OVX females the inhibitory effect of RU and MI was lower than that of ON. Uterine weights were not significantly decreased by MI, were significantly decreased by RU at a lower daily dose (50 µg) but not affected by a high (500 µg) dose. Seminal vesicle weights were increased by RU but not affected by MI in both NA-treated prepubertal and adult castrated males. In adult castrated but not in prepubertal males ON decreased seminal vesicle weights. In 17β-estradiol (E) plus progesterone (Prog)-treated animals of all four model systems, RU (100 µg/d) acted additively with a submaximal daily dose (10 µg) of antiestrogen ICI 182, 780 (ICI) to produce a lower mammary gland growth rate than ICI alone. In uterus, however, no significant effect of a combination of ICI plus RU was noted when compared with ICI alone. In general, our assay could serve as an in vivo tool for the detection of steroid hormone agonist and antagonist activities of newly synthesized analogs of steroid hormones, and natural and man-made chemicals and extracts of environmental samples.

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“…In the second part of this experiment, the GR agonist 11␤,17␤-dihydroxy-6,21-dimethyl-17␣-pregna-4,6-trien-20-yn-3-one (RU 28362) (1, 3, or 10 ng in 0.2 l; kindly provided by sanofi-aventis) was administered into the BLA alone or together with ␣-helical CRF 9 -41 (1 g). Receptor binding studies have shown that RU 28362 has selective and high affinity for GRs (Teutsch et al, 1981) but that RU 38486 has also known antiprogesterone activities (Philibert et al, 1991). Because RU 28362 and RU 38486 are lipophilic, the drug combinations were first dissolved in 100% ethanol and subsequently diluted in saline to reach a final ethanol concentration of 1%.…”

Section: Methodsmentioning

confidence: 99%

Corticotropin-Releasing Factor in the Basolateral Amygdala Enhances Memory Consolidation via an Interaction with the -Adrenoceptor-cAMP Pathway: Dependence on Glucocorticoid Receptor Activation

Roozendaal¹,

Schelling²,

McGaugh³

2008

Journal of Neuroscience

112

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Extensive evidence indicates that stress hormone effects on the consolidation of emotionally influenced memory involve noradrenergic activation of the basolateral complex of the amygdala (BLA). The present experiments examined whether corticotropin-releasing factor (CRF) modulates memory consolidation via an interaction with the ␤-adrenoceptor-cAMP system in the BLA. In a first experiment, male Sprague Dawley rats received bilateral infusions of the CRF-binding protein ligand inhibitor CRF 6 -33 into the BLA either alone or together with the CRF receptor antagonist ␣-helical CRF 9 -41 immediately after inhibitory avoidance training. CRF 6 -33 induced dose-dependent enhancement of 48 h retention latencies, which was blocked by coadministration of ␣-helical CRF 9 -41 , suggesting that CRF 6 -33 enhances memory consolidation by displacing CRF from its binding protein, thereby increasing "free" endogenous CRF concentrations. In a second experiment, intra-BLA infusions of atenolol (␤-adrenoceptor antagonist) and Rp-cAMPS (cAMP inhibitor), but not prazosin (␣ 1 -adrenoceptor antagonist), blocked CRF 6 -33 -induced retention enhancement. In a third experiment, the CRF receptor antagonist ␣-helical CRF 9 -41 administered into the BLA immediately after training attenuated the dose-response effects of concurrent intra-BLA infusions of clenbuterol (␤-adrenoceptor agonist). In contrast, ␣-helical CRF 9 -41 did not alter retention enhancement induced by posttraining intra-BLA infusions of either cirazoline (␣ 1 -adrenoceptor agonist) or 8-br-cAMP (cAMP analog). These findings suggest that CRF facilitates the memory-modulatory effects of noradrenergic stimulation in the BLA via an interaction with the ␤-adrenoceptorcAMP cascade, at a locus between the membrane-bound ␤-adrenoceptor and the intracellular cAMP formation site. Moreover, consistent with evidence that glucocorticoids enhance memory consolidation via a similar interaction with the ␤-adrenoceptor-cAMP cascade, a last experiment found that the CRF and glucocorticoid systems within the BLA interact in influencing ␤-adrenoceptor-cAMP effects on memory consolidation.

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From RU 38486 towards Dissociated Antiglucocorticoid and Antiprogesterone

Cited by 38 publications

References 0 publications

Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism

Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism

Biological Responses of Antiprogestins in Mammary Gland, Uterus and Seminal Vesicles of Prepubertal Intact and Adult Gonadectomized Mice

Corticotropin-Releasing Factor in the Basolateral Amygdala Enhances Memory Consolidation via an Interaction with the -Adrenoceptor-cAMP Pathway: Dependence on Glucocorticoid Receptor Activation

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