Partial deficiency or short-term inhibition of 11beta-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice. (2010)

Abstract

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11ß-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11ß-HSD1 knock-out mice, with ~60% reduction in hippocampal 11ß-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 11ß-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 11ß-HSD1 inhibitors in the treatment of age-related cognitive impairments.

Bibliographic Information

Digital Object Identifier: http://dx.doi.org/10.1523/JNEUROSCI.2783-10.2010

PubMed Identifier: 20943927

Publication URI: http://europepmc.org/abstract/MED/20943927

Type: Journal Article/Review

Volume: 30

Parent Publication: The Journal of neuroscience : the official journal of the Society for Neuroscience

Issue: 41

ISSN: 0270-6474