Elevated cortisol in Cushing's syndrome or ageing is associated with cognitive dysfunction. 11beta-HSD1 is expressed in rodent hippocampus and frontal cortex, regions important for cognition. In cultured rat hippocampal neurons, 11beta-HSD1 regenerates corticosterone from inert 11-dehydrocorticosterone and its inhibition by carbenoxolone is neuroprotective. 11beta-HSD1 knockout mice are protected against age-related cognitive dysfunction. We hypothesised that in elderly humans, 11beta-HSD1 inhibition with carbenoxolone will enhance cognitive function.Post-mortem sections (n=3-4/region) of human brain were obtained with ethical approval and relatives' consent from the Edinburgh Brain Bank. The subjects had no evidence of CNS disorders. 11beta-HSD1 mRNA was detected by in situ hybridisation using 35S-labelled cRNA in hippocampal neurons (dentate gyrus, cornu ammonis), prefrontal cortex and cerebellar granule cell layer. No signal was detected with similarly labelled 'sense' control RNA.10 healthy, unmedicated men (65.5 plus/minus 5.5y) participated in a randomised, double-blind, crossover trial comparing carbenoxolone (100 mg 8 hourly for 4 weeks, plus amiloride 10 mg daily to prevent renal mineralocorticoid excess) with placebo (plus amiloride 10 mg daily). Phases were separated by 8 weeks. At the end of each phase tests of verbal fluency, verbal memory, visuospatial memory, attention and processing speed, and intelligence were performed. Carbenoxolone improved verbal fluency (Controlled Word Association test; 41/12 vs 44/11, mean/SD, p<0.01) and verbal memory (Rey Auditory-Verbal Learning Test: p<0.03 by ANOVA), but did not significantly alter other cognitive tests.Thus, 11beta-HSD1 mRNA is expressed in human brain, notably in hippocampus and frontal cortex. Administration of carbenoxolone for just 4 weeks to healthy men improved aspects of cognition associated with hippocampal and frontal function. This most likely reflects reduced regeneration of cortisol from cortisone by 11beta-HSD1 within brain subregions. Inhibition of 11beta-HSD1 therefore provides an exciting new therapeutic target to prevent/ameliorate age-associated cognitive dysfunction in humans.
08 - 11 Apr 2002
British Endocrine Societies