Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

Abstract

Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11␤-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10 -30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ϳ35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

Integrating Transcriptomics with Metabolic Modeling Predicts Biomarkers and Drug Targets for Alzheimer's Disease

“…Intriguingly, the reaction that received the highest score within this pathway is 11-beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that catalyzes the intracellular regeneration of active glucocorticoids (i.e., cortisol and corticosterone). 11β-HSD1 knock-out mice have shown improved cognition, and 11β-HSD1 inhibitors improved memory in elderly men [48]. In general, steroids offer interesting therapeutic opportunities because of their varying roles in the nervous system: they regulate neurotransmitter systems, they promote the viability of neurons, and they influence cognitive processes [49].…”

Mifepristone Alters Amyloid Precursor Protein Processing to Preclude Amyloid Beta and Also Reduces Tau Pathology

“…Although these improvements are likely due to the marked reductions in both Aβ and tau pathologies in mifepristone-treated mice, anti-glucocorticoid drugs, through 11- hydroxy steroid dehydrogenase inhibitors, have recently been shown to improve cognition in aged mice of their own (43, 44). Of note, a small clinical trial in AD patients treated with mifepristone for just 6 weeks reported an increase in the ADAS-Cog (45), although this short timeframe is unlikely to have reversed pathology in humans.…”

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

“…In these tissues, increased local GC activation is postulated to contribute to the increased risk of fracture and osteoporosis and impaired cognitive function associated with aging. Improved cognition and increased long-term potentiation have been reported in aged 11β-HSD1 KO mice relative to age-matched controls (32), with improved memory consolidation, recall, and social recognition also reported following treatment with specific 11β-HSD1 inhibitors (33,34).…”