title: The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice.
abstract: Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.
authors.affiliation: Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Maria
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Dept. of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1425 Buenos Aires, Argentina.
authors.forename: Maria Claudia
authors.initials: MC
authors.lastname: Gonzalez Deniselle
authors.affiliation: Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, USA.
authors.forename: Hazel
authors.initials: H
authors.lastname: Hunt
authors.affiliation: LACDR/LUMC, Leiden University, Einstein weg 55, 2333 CC Leiden, The Netherlands.
authors.forename: E Ronald
authors.initials: ER
authors.lastname: de Kloet
authors.affiliation: Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, Argentina; Dept. of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1425 Buenos Aires, Argentina. Electronic address: alejandrodenicola@gmail.com.
authors.forename: Alejandro F
authors.initials: AF
authors.lastname: De Nicola
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001372:Aza Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003345:Corticosterone / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006624:Hippocampus / Q000002:abnormalities / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001372:Aza Compounds; C558517:CORT 108297; C000714328:DCX protein, human; D004268:DNA-Binding Proteins; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D006576:Heterocyclic Compounds, 4 or More Rings; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009479:Neuropeptides; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D003345:Corticosterone
keywords: Astrogliosis; CORT108297; Corticosterone; Glucocorticoid receptor antagonist; Hippocampus; Microglia; Neurogenesis; Wobbler mice