11β-Hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics
- Thekkepat C. Sandeep*,
- Joyce L. W. Yau*,
- Alasdair M. J. MacLullich†,
- June Noble*,
- Ian J. Deary‡,
- Brian R. Walker*, and
- Jonathan R. Seckl*,§
- *Endocrinology Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; †Geriatric Medicine, University of Edinburgh, Room SU220, The Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom; and ‡School of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, United Kingdom
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Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved January 23, 2004 (received for review October 29, 2003)
Abstract
In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11β-HSD1, but not 11β-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11β-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. 11β-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.
Footnotes
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↵ § To whom correspondence should be addressed. E-mail: j.seckl{at}ed.ac.uk.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: 11βHSD, 11β-hydroxysteroid dehydrogenase; HbA1c, glycosylated hemoglobin.
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See Commentary on page 6329.
- Copyright © 2004, The National Academy of Sciences
