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11[Beta]-hydroxysteroid dehydrogenase type 1 (11[Beta]-HSD-1) intracellularly regenerates active corticosterone from circulating inert 11-dehydrocorticosterone (11-DHC) in specific tissues. The hippocampus is a brain structure particularly vulnerable to glucocorticoid neurotoxicity with aging. In intact hippocampal cells in culture, 11[Beta]-HSD-1 acts as a functional 11[Beta]-reductase reactivating inert 11-DHC to corticosterone, thereby potentiating kainate neurotoxicity. We examined the functional significance of 11[Beta]-HSD-1 in the central nervous system by using knockout mice. Aged wild-type mice developed elevated plasma corticosterone levels that correlated with learning deficits in the watermaze. In contrast, despite elevated plasma corticosterone levels throughout life, this glucocorticoid-associated learning deficit was ameliorated in aged 11[Beta]-HSD-1 knockout mice, implicating lower intraneuronal corticosterone levels through lack of 11-DHC reactivation. Indeed, aged knockout mice showed significantly lower hippocampal tissue corticosterone levels than wild-type controls. These findings demonstrate that tissue corticosterone levels do not merely reflect plasma levels and appear to play a more important role in hippocampal functions than circulating blood levels. The data emphasize the crucial importance of local enzymes in determining intracellular glucocorticoid activity. Selective 11[Beta]-HSD-1 inhibitors may protect against hippocampal function decline with age.

Local brain amplification of glucocorticoids (GCs) by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a pivotal role in age-related memory deficits. 11β-HSD1 deficient mice are protected from spatial memory impairments with aging, but the underlying mechanisms are unknown. To determine which brain receptors [high-affinity mineralocorticoid receptors (MRs) or low-affinity glucocorticoid receptors (GRs)] are involved, spatial memory was measured in aged 11β-HSD1-/- mice before and during intracerebroventricular infusion (10 d) of spironolactone (MR antagonist) or RU486 (GR antagonist). Aged C57BL/6J control mice showed impaired spatial memory in the Y-maze; this improved with GR blockade, while MR blockade had no effect. In contrast, aged 11β-HSD1-/- mice showed intact spatial memory that became impaired with MR blockade, but not GR blockade. Hippocampal MR and GR mRNA expression and plasma corticosterone levels were not significantly altered with spironolactone or RU486 in either genotype. These data support the notion that 11β-HSD1 deficiency in aging mice leads to lower intracellular GC concentrations in brain, particularly in the hippocampus, which activate predominantly MRs to enhance memory, while in aging C57BL/6J controls, the increased intracellular GCs saturate MRs and activate predominantly GRs, thus impairing memory, an effect reversed by GR blockade. [ABSTRACT FROM AUTHOR]

β11-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. ExcessGCaction exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency of 11β-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11β-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11β-HSD1 knock-out mice, with ∼60% reduction in hippocampal 11β-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 11β-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 11β-HSD1 inhibitors in the treatment of age-related cognitive impairments. [ABSTRACT FROM AUTHOR]

Increased neuronal glucocorticoid exposure may underlie interindividual variation in cognitive function with aging in rodents and humans. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the regeneration of active glucocorticoids within cells (in brain and other tissues), thus amplifying steroid action. We examined whether 11β-HSD1 plays a role in the pathogenesis of cognitive deficits associated with aging in male C57BL/6J mice. We show that 11β-HSD1 levels increase with age in CA3 hippocampus and parietal cortex, correlating with impaired cognitive performance in the water maze. In contrast, neither circulating corticosterone levels nor tissue corticosteroid receptor expression correlates with cognition. 11β-HSD1 elevation appears causal, since aging (18 months) male transgenic mice with forebrain-specific 11β-HSD1 overexpression (~50% in hippocampus) exhibit premature age-associated cognitive decline in the absence of altered circulating glucocorticoid levels or other behavioral (affective) deficits. Thus, excess 11β-HSD1 in forebrain is a cause of as well as a therapeutic target in memory impairments with aging. [ABSTRACT FROM AUTHOR]

Increased neuronal glucocorticoid exposure may underlie interindividual variation in cognitive function with aging in rodents and humans. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the regeneration of active glucocorticoids within cells (in brain and other tissues), thus amplifying steroid action. We examined whether 11beta-HSD1 plays a role in the pathogenesis of cognitive deficits associated with aging in male C57BL/6J mice. We show that 11beta-HSD1 levels increase with age in CA3 hippocampus and parietal cortex, correlating with impaired cognitive performance in the water maze. In contrast, neither circulating corticosterone levels nor tissue corticosteroid receptor expression correlates with cognition. 11beta-HSD1 elevation appears causal, since aging (18 months) male transgenic mice with forebrain-specific 11beta-HSD1 overexpression ( approximately 50% in hippocampus) exhibit premature age-associated cognitive decline in the absence of altered circulating glucocorticoid levels or other behavioral (affective) deficits. Thus, excess 11beta-HSD1 in forebrain is a cause of as well as a therapeutic target in memory impairments with aging.

Pregnenolone (PREG) and dehydroepiandrosterone (DHEA) have been reported to improve memory in aged rodents. In brain, these neurosteroids are transformed predominantly into 7alpha-hydroxylated metabolites by the cytochrome P450-7B1 (CYP7B). The biological role of steroid B-ring hydroxylation is unclear. It has been proposed to generate bioactive derivatives that enhance cognition, immune, and other physiological processes. In support, 7alpha-hydroxylated DHEA increases the immune response in mice with greater potency than the parent steroid. Whether the memory-enhancing effects of PREG in rats is mediated via its 7alpha-hydroxylated metabolite 7alpha-hydroxyPREG is not known. We investigated this by treating memory-impaired aged rats (identified by their spatial memory performances in the Morris water maze task compared with young controls) with 7alpha-hydroxyPREG or PREG administered intracerebroventricularly using osmotic minipumps and then tested the rats during week 2 of steroid treatment in the eight-arm radial-arm version of the water maze (RAWM) that allows repeated assessment of learning. CYP7B bioactivity in hippocampal tissue (percentage conversion of [14C]DHEA to [14C]7alpha-hydroxyDHEA) was decreased selectively in memory-impaired aged rats compared with both young and memory-intact aged rats. 7alpha-hydroxyPREG (100 ng/h) but not PREG (100 ng/h) administration to memory-impaired aged rats for 11 d enhanced spatial memory retention (after a 30 min delay between an exposure trial 1 and test trial 2) in the RAWM. These data provide evidence for a biologically active enzyme product 7alpha-hydroxyPREG and suggests that reduced CYP7B function in the hippocampus of memory-impaired aged rats may, in part, be overcome by administration of 7alpha-hydroxyPREG.

Adult rats were given antidepressant drugs orally. Fluoxetine, but not moclobemide, venlafaxine, tianeptine or desipramine, increased total glucocorticoid receptor (GR) mRNA in the hippocampus after 4 weeks. Further examination revealed that GR mRNA containing the brain-specific exon 1(7) was increased across all hippocampal subregions. In contrast, expression of the major exon 1(10) and another brain-specific exon 1(5)-containing GR mRNAs were unchanged. Tissue-specific first exon usage may contribute to the differential regulation of GR by fluoxetine in brain subregions.

As rats age, a subgroup will show spatial memory impairments, along with decreased corticosteroid receptors (MR and/or GR) in the hippocampus and a hyperactive hypothalamic-pituitary-adrenal axis. In previous work, we have shown that amitriptyline treatment increases hippocampal MR mRNA and improves spatial memory in young rats but had no effect in aged rats. Here, we examine the effect of 1-month treatment with the selective 5-HT re-uptake inhibitor, fluoxetine (10 mg/kg, p.o.) on hippocampal corticosteroid receptor mRNA and spatial memory in young 4-month-old and aged 24-month-old rats. Aged rats were impaired in spatial memory compared to young controls. MR mRNA expression was reduced with ageing in all hippocampal subfields except CA4 (35% decrease in dentate gyrus (DG) and CA2, P<0.05) and GR mRNA was decreased selectively in CA1 (17% decrease, P<0.05). Fluoxetine treatment increased GR mRNA in the hippocampus of young rats (24 and 46% increase in DG and CA3, respectively, P<0.01) but had no effect on hippocampal MR mRNA expression. In contrast, in aged rats, fluoxetine treatment increased hippocampal MR mRNA selectively in CA2 (43% increase, P<0.05), but had no effect on hippocampal GR mRNA. Fluoxetine treatment did not alter watermaze performance in either young or aged rats. It appears that increased hippocampal MR (at least in the CA2 region) which may underlie the enhancement in memory processing in young rats, is insufficient to improve memory in already cognitively impaired aged rats.