title: Acute inhibition of 11beta-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. 11β-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 ∼ 35-90%. 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.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. Eric.Mohler@Abbott.com
authors.forename: Eric G
authors.initials: EG
authors.lastname: Mohler
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Browman
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Roderwald
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Cronin
authors.forename: Stella
authors.initials: S
authors.lastname: Markosyan
authors.forename: R
authors.initials: R
authors.lastname: Scott Bitner
authors.forename: Marina I
authors.initials: MI
authors.lastname: Strakhova
authors.forename: Karla U
authors.initials: KU
authors.lastname: Drescher
authors.forename: Wilfried
authors.initials: W
authors.lastname: Hornberger
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rohde
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: Peer B
authors.initials: PB
authors.lastname: Jacobson
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Rueter
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D050882:CREB-Binding Protein / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006854:Hydrocortisone / Q000378:metabolism; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D017551:Microdialysis / Q000379:methods; D023421:Models, Animal; D009483:Neuropsychological Tests; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012919:Social Behavior
chemical_list: D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D050882:CREB-Binding Protein; D006854:Hydrocortisone