Glucocorticoid metabolism and the brain, from fetal programming to senescence
Jonathan R Seckl
Chronic elevation of glucocorticoids adversely impacts on cognition and the integrity of hippocampal cells. Moreover, inter-individual differences in memory with ageing correlate directly with blood glucocorticoid levels in rodents and humans. Beyond plasma steroid levels, glucocorticoid action on target tissues is determined by the density of nuclear receptors and by intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs) which catalyse interconversion of active cortisol (corticosterone in rodents) and inert cortisone (11-dehydrocorticosterone). In the fetal CNS and placenta 11β-HSD2 predominates. This isozyme catalyses the rapid inactivation of glucocorticoids and acts as a barrier to steroid access to receptors. Inhibition, knockout, bypass or down-regulation (maternal stress, inflammation or malnutrition) of feto-placental 11β-HSD2 allows excess glucocorticoid action on the fetus which programmes many organs, notably the brain. The offspring show affective and cognitive deficits throughout life. Similar effects are seen in the offspring of women who consume liquorice-based 11β-HSD inhibitors in gestation.
In the adult brain 11β-HSD type 1 predominates. This catalyses the reverse reaction, regenerating active steroids and thus amplifying intracellular glucocorticoid action. 11β-HSD1 inhibition protects hippocampal cells from neurotoxic challenge in vitro. 11β-HSD1 is elevated in aged rat hippocampus and correlates with the degree of cognitive decline suggesting an aetiological role. Importantly, 11β-HSD1 null mice resist glucocorticoid-associated cognitive impairments with ageing. Indeed the 11β-HSD inhibitor carbenoxolone improves cognitive performance in elderly humans. Early results suggest selective 11β-HSD1 inhibitors improve memory in aged rodents and even modify pathogenesis in models of Alzheimers disease. 11β-HSD1 inhibition appears a promising target for therapy of age-related cognitive disorders.