Partial Deficiency or Short-Term Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Cognitive Function in Aging Mice

K. Sooy, S. P. Webster, J. Noble, M. Binnie, B. R. Walker, J. R. Seckl, J. L. W. Yau

Research output: Contribution to journalArticlepeer-review

Abstract

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. Excess GC action exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency of 11 beta-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11 beta-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11 beta-HSD1 knock-out mice, with similar to 60% reduction in hippocampal 11 beta-reductase activity throughout life, were protected against spatial memory impairments in the Y-maze compared to age-matched congenic C57BL/6J controls. Pharmacological treatment of aged C57BL/6J mice with a selective 11 beta-HSD1 inhibitor (UE1961) for 10 d improved spatial memory performance in the Y-maze (59% greater time in novel arm than vehicle control). These data support the use of selective 11 beta-HSD1 inhibitors in the treatment of age-related cognitive impairments.

Original languageEnglish
Pages (from-to)13867-13872
Number of pages6
JournalThe Journal of Neuroscience
Volume30
Issue number41
DOIs
Publication statusPublished - Oct 2010

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