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

Abstract

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.

Compound library development guided by protein structure similarity clustering and natural product structure

“…11␤HSD1 may be a promising therapeutic target for the antagonization of glucocorticoid actions (39,41). Its inhibition is considered to be a promising approach to the treatment of obesity (30,42), the metabolic syndrome (43,44), diabetes type 2 (45,46), and cognitive dysfunction (47). The 11␤HSD2 isoform catalyzes exclusively the oxidation of cortisol, and inhibition of 11␤HSD2 causes sodium retention resulting in hypertension (48).…”

Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11β-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice

“…Although compatible with the notion that reduced 11␤-HSD1 activity is beneficial, this finding leaves open the question as to whether this is a cognitive or perceptual effect. Intriguingly, the 11␤-HSD inhibitor carbenoxolone improves aspects of cognitive function in humans (Sandeep et al, 2004). Whether these effects in mice and humans reflect direct or indirect (e.g., metabolic) actions on the brain is uncertain.…”

“…11␤-HSD2 is barely expressed in the adult CNS. In contrast, 11␤-HSD type 1 is highly expressed in liver and adipose tissue and is the major isozyme in the adult brain in rodents (Moisan et al, 1990) and humans (Sandeep et al, 2004). Although 11␤-HSD1 is bidirectional in tissue homogenates, in intact cells, including neurons, 11␤-HSD1 is a reductase, catalyzing regeneration of active GCs [cortisol in humans; corticosterone (CORT) in rodents] from inert circulating 11-keto forms [cortisone; 11-dehydrocorticosterone (11-DHC)], themselves produced by renal 11␤-HSD2.…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…These data highlighted 11β-HSD1 as a promising drug target for treatment of insulin resistance, diabetes and even cardiovascular disease. Indeed, to date, over 100 patents exist on 11β-HSD1 inhibitors and initial data, at least for the treatment of diabetes (Alberts et al, 2003;Wang et al, 2006) and atheroma (HermanowskiVosatka et al, 2005), and even, possibly, improvement of cognitive function (Sandeep et al, 2004) appear promising. Thus, paradoxically, deficiency in 11β-HSD1 is associated with worsened acute inflammation yet inhibition improves outcome in chronic inflammatory conditions often associated with over-nutrition.…”