Differential inhibition of 11β-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues

Jellinck, Peter H.; Monder, Carl; McEwen, Bruce S.; Sakai, Randall R.

doi:10.1016/0960-0760(93)90296-9

Cited by 76 publications

(46 citation statements)

References 19 publications

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“…Carbenoxolone, a widely used 11␤-HSD inhibitor, effectively inhibits both 11␤-HSD2 and 11␤-HSD1 in the periphery in humans (28,36), as well as 11␤-HSD1 in the rodent hippocampus in vitro and in vivo (35,38). Carbenoxolone also inhibits other dehydrogenases and interferes with gap junction formation, but such actions require concentrations (10 Ϫ5 to 10 Ϫ4 M) several orders of magnitude higher than needed to inhibit 11␤-HSD (typically 10 Ϫ9 M in vitro) and are unlikely to have been achieved in this in vivo study (30).…”

Section: Discussionmentioning

confidence: 99%

11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

Sandeep

Yau

MacLullich

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

228

173

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In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11␤-HSD1, but not 11␤-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebocontrolled crossover studies, administration of the 11␤-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11␤-HSD1 inhibition may be a new approach to prevent͞ameliorate cognitive decline.

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Section: Discussionmentioning

confidence: 99%

11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

Sandeep

Yau

MacLullich

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

228

173

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“…The reaction was stopped with perchloric acid and the samples were centrifuged at 1300 g for 3 min. 3 H-Cortisol and 3 H-cortisone in the supernatant were separated by HPLC (HP1100; Hewlett-Packard, Palo Alto, Calif., USA; 15 µl injection volume, 5 µm diameter C18 column; acetonitrile:water 28:72, 0.8 ml/min) [22]. Radioactivity was measured by adding scintillation cocktail (Ultima-Flo, Packard, Meriden, Conn., USA) to the effluent and passed through an on-line liquid scintillation spectrometer (Flow scintillation analyser, Packard).…”

Section: Methodsmentioning

confidence: 99%

Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

et al. 2002

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Aims/hypothesis. Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11β-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11β-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. Methods.BVT.2733 was given to spontaneously hyperglycaemic KKA y mice for 7 days using subcutaneous osmotic mini-pumps. Results. BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11β-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. Conclusion/interpretation. These results suggest that a selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1528[Diabetologia ( -1532

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“…In addition, this agent has been widely used as a mineralocorticoid agonist to inhibit 11-beta hydroxysteroid dehydrogenase and block gap-junction communication in various experimental studies [15,22,23] .…”

Section: Introductionmentioning

confidence: 99%

Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury

Zhang

Jing

et al. 2013

Neurosci. Bull.

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Accumulating evidence has suggested that the gap junction plays an important role in the determination of cerebral ischemia, but the underlying mechanisms remain to be elucidated. In this study, we assessed the effect of a gap-junction blocker, carbenoxolone (CBX), on ischemia/reperfusion-induced brain injury and the possible mechanisms. By using the transient cerebral ischemia model induced by occlusion of the middle cerebral artery for 30 min followed by reperfusion for 24 h, we found that pre-administration of CBX (25 mg/kg, intracerebroventricular injection, 30 min before cerebral ischemic surgery) diminished the infarction size in rats. And this was associated with a decrease of reactive oxygen species generation and inhibition of the activation of astrocytes and microglia. In PC12 cells, H 2 O 2 treatment induced more coupling and apoptosis, while CBX partly inhibited the opening of gap junctions and improved the cell viability. These results suggest that cerebral ischemia enhances the opening of gap junctions. Blocking the gap junction with CBX may attenuate the brain injury after cerebral ischemia/reperfusion by partially contributing to amelioration of the oxidative stress and apoptosis.

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Differential inhibition of 11β-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues

Cited by 76 publications

References 19 publications

11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

Protective effects of carbenoxolone are associated with attenuation of oxidative stress in ischemic brain injury

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