Chronic elevation of plasma glucocorticoids adversely affects cognitive processes and the structural and functional integrity of the hippocampus. Crucially, inter-individual differences in memory with ageing directly associate with blood glucocorticoid levels in rodents and humans; indeed higher plasma corticosterone in mid-life in rodents predict subsequent memory impairments. However, although keeping glucocorticoid levels low by adrenalectomy in adult life prevents the emergence of memory impairments with age in rats, such prophylactic surgery is not a practical alternative in human therapy, not least because glucocorticoid deficiency is also harmful.
Recent data suggest that pre-receptor metabolism by 11ß-hydroxysteroid dehydrogenases (11ß-HSDs), which interconvert active glucocorticoids and inert 11-keto metabolites, potently regulates glucocorticoid action in specific cells in vivo, including in CNS. The brain highly expresses 11ß-HSD type 1, an 11β-reductase in intact hippocampal neurons and glia which regenerates active steroids and thus locally amplifies glucocorticoid action. Inhibition of 11ß-HSD1 protects hippocampal cells from neurotoxic challenge in vitro. Young 11ß-HSD1−/− mice, despite elevated plasma corticosterone levels, perform as well as young wild-type animals, suggesting they are relatively blind to the tissue effects of elevated plasma glucocorticoids. Strikingly, aged 11ß-HSD1 null mice also learn as well as young mice and avoid the cognitive decline seen in the majority of aged wild-type mice. In explanation, despite maintained plasma corticosterone, aged 11ß-HSD1−/− mice have markedly reduced intrahippocampal corticosterone levels. 11ß-HSD1 is also expressed in the adult human CNS. In two small, randomised, double-blind, placebo-controlled, cross-over studies, administration of the 11ß-HSD inhibitor carbenoxolone improved verbal fluency after four weeks in ten healthy elderly men and improved verbal memory after six weeks in 12 patients with type 2 diabetes. Thus 11ß-HSD1 may be a useful therapeutic target in age-related cognitive disorders and is a prototype for tissue-specific manipulation of the effects of steroids in brain and peripheral tissues.