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      From The Cover: 11 -Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

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          Abstract

          In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11beta-HSD1, but not 11beta-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11beta-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. 11beta-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.

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          Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation.

          J Reul, E. de Kloet (1985)
          Two receptor systems for corticosterone (CORT) can be distinguished in rat brain: mineralocorticoid-like or CORT receptors (CR) and glucocorticoid receptors (GR). The microdistribution and extent of occupation of each receptor population by CORT were studied. The CR system is restricted predominantly to the lateral septum and hippocampus. Within the hippocampus, the highest density occurs in the subiculum +/- CA1 cell field (144 fmol/mg protein) and the dentate gyrus (104 fmol/mg protein). Affinity of CR for CORT was very high (Kd, approximately 0.5 nM). The GR system has a more widespread distribution in the brain. The highest density for GR is in the lateral septum (195 fmol/mg protein), the dentate gyrus (133 fmol/mg protein), the nucleus tractus solitarii and central amygdala. Substantial amounts of GR are present in the paraventricular nucleus and locus coeruleus and low amounts in the raphe area and the subiculum + CA1 cell field. The affinity of GR for CORT (Kd, approximately 2.5-5 nM) was 6- to 10-fold lower than that of CR. Occupation of CR by endogenous ligand was 89.5% during morning trough levels of pituitary-adrenal activity (plasma CORT, 1.4 micrograms/100 ml). Similar levels of occupation (88.7% and 97.6%) were observed at the diurnal peak (plasma CORT, 27 micrograms/100 ml) and after 1 h of restraint stress (plasma CORT, 25 micrograms/100 ml), respectively. Furthermore, a dose of 1 microgram CORT/100 g BW, sc, resulted in 80% CORT receptor occupation, whereas GR were not occupied. For 50% occupation of GR, doses needed to be increased to 50-100 micrograms/100 g BW, and for 95% occupation, a dose of 1 mg CORT was required. The plasma CORT level at the time of half-maximal GR occupation was about 25 micrograms/100 ml, which is in the range of levels attained after stress or during the diurnal peak of pituitary-adrenal activity. Thus, CR are extensively filled (greater than 90%) with endogenous CORT under most circumstances, while GR become occupied concurrent with increasing plasma CORT concentrations due to stress or diurnal rhythm. We conclude that CORT action via CR may be involved in a tonic (permissive) influence on brain function with the septohippocampal complex as a primary target. In view of the almost complete occupation of CR by endogenous hormones, the regulation of the CORT signal via CR will, most likely, be by alterations in the number of such receptors. In contrast, CORT action via GR is involved in its feedback action on stress-activated brain mechanisms, and GR occur widely in the brain.(ABSTRACT TRUNCATED AT 400 WORDS)
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            Cortisol levels during human aging predict hippocampal atrophy and memory deficits.

            S J Lupien, M. de León, S De Santi … (1998)
            Elevated glucocorticoid levels produce hippocampal dysfunction and correlate with individual deficits in spatial learning in aged rats. Previously we related persistent cortisol increases to memory impairments in elderly humans studied over five years. Here we demonstrate that aged humans with significant prolonged cortisol elevations showed reduced hippocampal volume and deficits in hippocampus-dependent memory tasks compared to normal-cortisol controls. Moreover, the degree of hippocampal atrophy correlated strongly with both the degree of cortisol elevation over time and current basal cortisol levels. Therefore, basal cortisol elevation may cause hippocampal damage and impair hippocampus-dependent learning and memory in humans.
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              Does central obesity reflect "Cushing's disease of the omentum"?

              I J Bujalska, S Kumar, P M Stewart (1997)
              Central obesity results in a cluster of metabolic abnormalities contributing to premature death. Glucocorticoids regulate adipose-tissue differentiation, function, and distribution, and in excess, cause central obesity. Glucocorticoid hormone action is, in part, controlled by two isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) which interconverts hormonally active cortisol to inactive cortisone. We studied cortisol metabolism within different adipose tissue depots. We analysed expression and activity of the two isoforms (1 and 2) of 11 beta-HSD in cultured omental and subcutaneous adipose stromal cells from 16 patients undergoing elective abdominal surgery. Only the type 1 isoform (11 beta-HSD1) was expressed in adipose stromal cells. The predominant activity was oxo-reductase (conversion of cortisone to cortisol greater than cortisol to cortisone) and was higher in omental than subcutaneous fat (cortisone to cortisol, median 57.6 pmol mg-1 h-1 [95% CI 25.8-112.9] vs 0 pmol mg-1 h-1 [0-0.6], p < 0.001). 11 beta-HSD1 oxo-reductase activity was further increased (127.5 pmol mg-1 h-1 [82.1-209], p < 0.05) when omental adipose stromal cells were treated with cortisol and insulin. Adipose stromal cells from omental fat, but not subcutaneous fat, can generate active cortisol from inactive cortisone through the expression of 11 beta-HSD1. The expression of this enzyme is increased further after exposure to cortisol and insulin. In vivo, such a mechanism would ensure a constant exposure of glucocorticoid specifically to omental adipose tissue, suggesting that central obesity may reflect "Cushing's disease of the omentum".
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                Author and article information

                Journal
                Title: Proceedings of the National Academy of Sciences
                Abbreviated Title: Proceedings of the National Academy of Sciences
                Publisher: Proceedings of the National Academy of Sciences
                ISSN (Print): 0027-8424
                ISSN (Electronic): 1091-6490
                Publication date Created: April 27 2004
                Publication date Created: April 27 2004
                Publication date (Electronic): April 07 2004
                Publication date (Print): April 27 2004
                Volume: 101
                Issue: 17
                Pages: 6734-6739
                Article
                DOI: 10.1073/pnas.0306996101
                PMC ID: 404114
                PubMed ID: 15071189
                SO-VID: 845c9b41-f772-4e3e-8fff-8d202d5cad20
                Copyright © © 2004
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