Search

Glucocorticoid (GC) excess drives multiple cutaneous adverse effects, including skin thinning and poor wound healing. The ubiquitously expressed enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates mouse corticosterone from 11-dehydrocorticosterone (and human cortisol from cortisone). We previously demonstrated elevated 11β-HSD1 activity during mouse wound healing, but the interplay between cutaneous 11β-HSD1 and systemic GC excess is unexplored. Here, we examined effects of 11β-HSD1 inhibition by carbenoxolone (CBX) in mice treated with corticosterone (CORT) or vehicle for 6 weeks. Mice were treated bidaily with topical CBX or vehicle (VEH) 7 days before wounding and during wound healing. CORT mice displayed skin thinning and impaired wound healing but also increased epidermal integrity. 11β-HSD1 activity was elevated in unwounded CORT skin and was inhibited by CBX. CORT mice treated with CBX displayed 51%, 59%, and 100% normalization of wound healing, epidermal thickness, and epidermal integrity, respectively. Gene expression studies revealed normalization of interleukin 6, keratinocyte growth factor, collagen 1, collagen 3, matrix metalloproteinase 9, and tissue inhibitor of matrix metalloproteinase 4 by CBX during wound healing. Importantly, proinflammatory cytokine expression and resolution of inflammation were unaffected by 11β-HSD1 inhibition. CBX did not regulate skin function or wound healing in the absence of CORT. Our findings demonstrate that 11β-HSD1 inhibition can limit the cutaneous effects of GC excess, which may improve the safety profile of systemic steroids and the prognosis of chronic wounds., (Copyright © 2018 Endocrine Society.)

1. One of the major causes of metabolic syndrome is elevated 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in the liver and adipose tissue. High 11β-HSD1 expression contributes significantly to the diabetic phenotype in db/db mice. The purpose of the present study was to test the effect of the pharmacological inhibition of 11β-HSD1 inhibition by carbenoxolone in db/db mice, a genetic model of diabetes. 2. Inhibition of 11β-HSD1 by carbenoxolone was evaluated in liver homogenates obtained from untreated mice. At 0.4, 0.8, 1.6 and 3.2 μmol/L, carbenoxolone reduced the conversion of cortisone to cortisol by 21%, 48%, 82% and 95%, respectively. 3. In another series of experiments in which female db/db mice were dosed orally with carbenoxolone (10, 25 and 50 mg/kg, twice daily) for 10 days, dose-dependent decreases were observed in 11β-HSD1 activity in the brain, adipose and liver. In the case of 10 mg/kg carbenoxolone, the effects were not significant. In addition, the bodyweight of female db/db mice was reduced by 10% and 13% following treatment with 10 and 50 mg/kg carbenoxolone, respectively. Carbenoxolone treatment dose-dependently improved fat mass, energy expenditure, the serum lipid profile, serum leptin and insulin and glucose tolerance. Furthermore, 50 mg/kg carbenoxolone reduced both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity in the liver by 75% and 52%, respectively. These decreases were associated with increased glucokinase protein expression and activity in the liver. 4. Carbenoxolone inhibition of 11β-HSD1 in the liver, adipose and brain significantly improves the symptoms of metabolic syndrome in db/db mice. These improvements can be attributed to increased energy expenditure, decreased activity of the gluconeogenic enzymes PEPCK and G6Pase in the liver and improved glucokinase function in the liver and pancreas., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)

Recent human epidemiological studies have linked low birth weight with a substantially increased risk of non-insulin-dependent diabetes mellitus in later life. These data suggest that the intrauterine environment plays a crucial role in determining later glucose homeostasis, but the mechanism is unknown. We have proposed that exposure of the fetus to excess maternal glucocorticoids may underpin the epidemiological findings. Normally placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2) protects the fetus from the normally higher maternal levels of glucocorticoids by inactivating corticosterone and cortisol to inert 11-keto products. Here we show that administration of carbenoxolone, an inhibitor of placental 11 beta-HSD 2, to pregnant rats, leads to a significant reduction in average birth weight (20% fall). At 6 months of age, the male offspring of carbenoxolone-treated pregnancies had similar weights to controls, but showed significantly higher fasting plasma glucose (6.0 +/- 0.3 vs 4.8 +/- 0.2 mmol/l; p < 0.01) and exhibited significantly greater plasma glucose (10% higher) and insulin (38% higher) responses to an oral glucose load. These effects of carbenoxolone require intact maternal adrenal glands suggesting that inhibition of feto-placental 11 beta-HSD 2 is key. These data support the notion that deficiency of placental 11 beta-HSD, by exposing the fetus to excess maternal glucocorticoids, reduces growth and predisposes to hyperglycaemia in later life.

Carbenoxolone (CX), the succinyl ester of glycyrrhetinic acid, causes hypokalemia and hypernatremia. Its pharmacological effects are believed to be due to its inhibition of 11 beta-hydroxysteroid dehydrogenase (11-HSD). There was a marked inhibition of this enzyme in the liver, kidney, pituitary, hippocampus, hypothalamus and amygdala 1 h after intraperitoneal administration of CX (100 mg kg-1) to intact male rats. Intracerebral injection of CX (1.5 mg kg-1) into the 3rd ventricle inhibited the oxidation of corticosterone to 11-dehydrocorticosterone by 11-HSD in the pituitary and hippocampus and produced marked behavioral hyperactivity but had no effect in the liver or kidney. Lower amounts of CX (10-50 micrograms/rat) given intracerebroventricularly (i.c.v) were without significant effect on 11-HSD in the pituitary or amygdala 1 h after infusion but inhibited this enzyme differentially in the hippocampus and hypothalamus. Inhibition of 11-HSD activity in the hippocampus and hypothalamus was observed up to 6 h after i.c.v. administration of CX (50 micrograms/rat) together with some decrease in activity of this enzyme in the pituitary at 3 h. The findings that low doses of CX given i.c.v. can alter the activity of 11-HSD in specific brain regions without affecting its activity in peripheral tissues, and only marginally in the pituitary, provides a method to study the central role of this enzyme independently of systemic effects.