title: New selective glucocorticoid receptor modulators reverse amyloid-β peptide-induced hippocampus toxicity.
abstract: In Alzheimer's disease (AD), cognitive deficits and psychological symptoms are associated with an early deregulation of the hypothalamic-pituitary-adrenal axis. Here, in an acute model of AD, we investigated if antiglucocorticoid strategies with selective glucocorticoid receptor (GR) modulators (CORT108297 and CORT113176) that combine antagonistic and agonistic GR properties could offer an interesting therapeutic approach in the future. We confirm the expected properties of the nonselective GR antagonist (mifepristone) because in addition to restoring basal circulating glucocorticoids levels, mifepristone totally reverses synaptic deficits and hippocampal apoptosis processes. However, mifepristone only partially reverses cognitive deficit, effects of the hippocampal amyloidogenic pathway, and neuroinflammatory processes, suggesting limits in its efficacy. By contrast, selective GR modulators CORT108297 and CORT113176 at a dose of 20 and 10 mg/kg, respectively, reverse hippocampal amyloid-β peptide generation, neuroinflammation, and apoptotic processes, restore the hippocampal levels of synaptic markers, re-establish basal plasma levels of glucocorticoids, and improve cognitive function. In conclusion, selective GR modulators are particularly attractive and may pave the way to new strategies for AD treatment.
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U1198, Montpellier, France; University of Montpellier, Montpellier, France; EPHE, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Pineau
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U1198, Montpellier, France; University of Montpellier, Montpellier, France; EPHE, Paris, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Canet
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U1198, Montpellier, France; University of Montpellier, Montpellier, France; EPHE, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Desrumaux
authors.affiliation: Corcept Therapeutics, Menlo Park, CA, USA.
authors.forename: Hazel
authors.initials: H
authors.lastname: Hunt
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U1198, Montpellier, France; University of Montpellier, Montpellier, France; EPHE, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chevallier
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U1198, Montpellier, France; University of Montpellier, Montpellier, France; EPHE, Paris, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ollivier
authors.affiliation: Corcept Therapeutics, Menlo Park, CA, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Belanoff
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U1198, Montpellier, France; University of Montpellier, Montpellier, France; EPHE, Paris, France. Electronic address: lgivalois@univ-montp2.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D060825:Cognitive Dysfunction / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000097:blood; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007030:Hypothalamo-Hypophyseal System; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D015735:Mifepristone / Q000494:pharmacology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D010913:Pituitary-Adrenal System; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors*
chemical_list: D016229:Amyloid beta-Peptides; D001372:Aza Compounds; C558517:CORT 108297; C000623379:CORT113176; D005938:Glucocorticoids; D006576:Heterocyclic Compounds, 4 or More Rings; D007546:Isoquinolines; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; D015735:Mifepristone
keywords: Alzheimer's disease; Amyloid-β peptide; Aβ(25–35) peptide; Glucocorticoid receptors; HPA axis; Hippocampus; Rat; Selective GR modulator