Targeting 11β-hydroxysteroid dehydrogenase type 1 in brain: therapy for cognitive aging?

Abstract

Dementia care costs exceed those of cardiovascular diseases and cancer combined. Milder forms of functionally significant cognitive decline add further to the staggering human, societal and economic costs. However, the underlying mechanisms are poorly understood and few treatments are available. Cumulative exposure to high glucocorticoid levels is a major hypothesis of decline in cognitive function with aging. Current manipulations to maintain low circulating glucocorticoid levels throughout life (adrenalectomy with low-dose corticosterone replacement and neonatal handling), although effective in preventing the emergence of memory deficits with age in rodent models, are not clinically applicable. By contrast, recent data in cells, mice and humans suggest that inhibition of the tissue-selective glucocorticoid-amplifying enzyme, 11β-hydroxysteroid dehydrogenase type 1, may be an effective novel approach.

Keywords::

• 11β-hydroxysteroid dehydrogenase
• carbenoxolone
• glucocorticoid receptor
• glucocorticoids
• hippocampus
• hypothalamic–pituitary–adrenal axis
• spatial memory