Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n = 8) received one of the following: CORT 108297 (80 mg/kg QD), CORT 108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain

Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n = 8) received one of the following: CORT 108297 (80 mg/kg QD), CORT 108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, highsugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain

Development of specific glucocorticoid receptor antagonists

Background / Methods : Mifepristone, a potent glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, has recently become the first medication approved for the treatment of Cushing's syndrome, the archetypal illness of cortisol excess. Mifepristone is also being studied for the treatment of psychotic depression in a Phase 3 study and in numerous academic studies on diseases in which GR antagonism is thought to be potentially useful. In all cases, mifepristone utility is generated by its ability to block GR and its antagonism of PR is either irrelevant or troublesome. A selective GR antagonist may confer the same benefits of mifepristone while removing an important liability. Results : Data are provided from animal and human studies of mifepristone and animal studies of novel, selective GR antagonists in metabolic and psychiatric diseases. Conclusions : Pre-clinical studies indicate that selective GR antagonists may potentially have the same clinical utility as mifepristone in blocking cortisol while eliminating the unwanted effects of progesterone blockade

An open label trial of C-1073 (mifepristone) for psychotic major depression

BACKGROUND: The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained. METHODS: Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days. RESULTS: All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group. CONCLUSIONS: These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted

C113176 treatment maintains body mass while RU486 increases body mass with ROD treatment.

<p>Animal body mass (g) were recorded every two days for 10 days as a measure of fold change from day 0, pellet surgery (A). Animal body mass on day 10 was measured as a percent change of body mass from day 0 (B). The dotted line (100%) represents no change in body mass from day 0. Arrow indicates that 2 days after pellet surgeries respective antagonists or vehicle were administered at 80 mg/kg/day to each treatment group. Bars that do not share similar letters denote statistical significance, p<0.05, one-way ANOVA using Tukey's post-hoc test. n = 7–10. All values are means ± SE.</p

Glucose intolerance and acute insulin response (AIR) is improved with RU486 and C113176 treatment.

<p>Fasting (basal, 0 minutes) and stimulated blood glucose levels (mM) were measured at 5, 15, 30, 60, 90 and 120 minutes post oral glucose gavage (A). Glucose area under the curve (AUC) was calculated based on fasting blood glucose of individual animals (A′). Fasting (basal, 0 minutes) and glucose-stimulated insulin levels (ng/ml) were measured at 15, 30, 60, and 120 minutes post oral glucose gavage (B). Insulin area under the curve (AUC) was calculated based on fasting individual insulin levels within each group (B′). To measure insulin capacity acute insulin response (AIR) was measured by the difference in insulin levels between fasting insulin and 15 minutes post glucose gavage (C). Negative values represent a decrease in insulin response, indicating impairment in insulin secretion. Bars that do not share similar letters denote statistical significance, p<0.05, one-way ANOVA using Tukey's post-hoc. A student's unpaired t-test was performed between controls and ROD, C108297 and C113176 groups (C). n = 7–10. All values are means ± SE.</p

11β-HSD1 content in visceral fat is attenuated with RU486 treatment but not with C113176 or C108297 treatment.

<p>No changes were found in lipolytic protein levels with treatment of antagonists. 11β-HSD1 content was measured in epididymal fat pads to represent visceral adipose tissue and expressed relative to α-tubulin content (A). CD36 protein levels were measured from epididymal fat pads (B) as well as adipose triglyceride lipase (ATGL) (C) and hormone-sensitive lipase (HSL) (D) protein levels as markers of lipolytic adipose tissue activity and expressed relative to loading control. Bars that do not share similar letters denote statistical significance, p<0.05 one-way ANOVA using Tukey's post-hoc test. n = 5–6. All values are means ± SE.</p

Anthropometric data for epididymal fat pad, liver, heart, epitrochlearis, soleus and tibialis anterior mass (g/kg of body mass).

<p>Note: Different letters denote statistical significance, p<0.05, n = 6–10. All values are means ± SE.</p

Fed and fasting glucose, insulin, and non-esterified fatty acids (NEFAs) levels on day 12.

<p>Note: Different letters denote statistical significance, p<0.05, n = 6–10. All values are means ± SE.</p

Glucose stimulated insulin secretion (GSIS) was normalized with RU486 and C113176 treatment.

<p>GSIS in isolated islets was measured in low (2.8 mM) and high (16.7 mM) glucose media for 1-hour incubations expressed as ng/ml/islet/hour. Bars that do not share similar letters denote statistical significance, p<0.05 one-way ANOVA using student's unpaired t-test. n = 3–7. All values are means ± SE.</p