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• W2017494051 abstract "A growing body of evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates conversion of glucocorticoids from inactive to active forms. 11β-HSD1 knock-out mice have improved cognition and the non-selective inhibitor carbenoxolone improved verbal memory in elderly men. Taken together, these data suggest that 11β-HSD1 inhibition may be a potential new therapy for cognitive deficits associated with AD. We characterized two novel 11β-HSD1 inhibitors, A-918446 and A-801195. Mice were treated with A-918446 in diet for 18 days, tested in a 24-hour inhibitory avoidance (IA) test that measures memory consolidation/recall and then sacrificed to examine cAMP response element binding protein (CREB) phosphorylation in the cingulate cortex. To investigate the efficacy of acute administration, mice received A-918446 one hour before training in the IA test or before tissue collection. In rats, A-801195 was administered one hour before testing in a social recognition assay that measures short-term memory. Inhibition of brain cortisol production by A-801195 one hour post acute dosing was examined using an ex-vivo assay. Cortical and hippocampal acetylcholine release was measured via in vivo microdialysis in rats receiving acute A-801195. Dietary A-918446 (10 or 100 mg/kg/day for 18 days) improved memory consolidation and increased CREB phosphorylation in the cingulate cortex (100 mg/kg/day dose only) in mice. Furthermore, acute A-918446 (0.3-30 mg/kg) induced a dose-dependent improvement in memory consolidation/recall and increased cortical CREB phosphorylation. In rats, acute A-801195 (10 and 30 mg/kg, but not 3 mg/kg) significantly improved short-term memory. Efficacious doses of A-801195 (10 and 30 mg/kg) acutely inhibited brain cortisol production while a non-efficacious dose (3 mg/kg) did not. The cognitive improvement induced by 11β -HSD1 inhibitors is not likely a result of alterations to the cholinergic system, as no changes in cortical or hippocampal acetylcholine levels were observed in rats after treatment with A-801195 (30 mg/kg). These studies demonstrate that 11β-HSD1 inhibitors induce cognitive enhancement in two species and multiple cognitive domains through a novel, non-cholinergic mechanism, thereby suggesting that 11β-HSD1 inhibitors may be useful for the treatment of cognitive dysfunction associated with AD." @default.
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• W2017494051 date "2010-07-01" @default.
• W2017494051 modified "2023-09-27" @default.
• W2017494051 title "P3-302: Cognitive effects of 11beta-hydroxysteroid dehydrogenase1 inhibitors are accompanied by changes in CREB phosphorylation and glucocorticoid inhibition" @default.
• W2017494051 doi "https://doi.org/10.1016/j.jalz.2010.05.1803" @default.
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