The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice

Autor: Maria Meyer, E. Ronald de Kloet, Hazel Hunt, Maria Claudia Gonzalez Deniselle, Alejandro F. De Nicola
Rok vydání: 2014
Předmět:
Doublecortin Domain Proteins
Glucocorticoid receptor antagonist
Endocrinology
Diabetes and Metabolism
Clinical Biochemistry
Anti-Inflammatory Agents
Fluorescent Antibody Technique
Hippocampus
Astrogliosis
Hippocampal formation
Biochemistry
GLUCOCORTICOID RECEPTOR ANTAGONIST
Immunoenzyme Techniques
Mice
Endocrinology
Cells
Cultured
Neurons
Glial fibrillary acidic protein
biology
Chemistry
Nuclear Proteins
Bioquímica y Biología Molecular
CORT 108297
DNA-Binding Proteins
Medicina Básica
medicine.anatomical_structure
Molecular Medicine
Female
Microglia
Microtubule-Associated Proteins
Astrocyte
medicine.medical_specialty
CIENCIAS MÉDICAS Y DE LA SALUD
Doublecortin Protein
Neurogenesis
Neurociencias
Blotting
Western
Nerve Tissue Proteins
Heterocyclic Compounds
4 or More Rings
Mice
Neurologic Mutants
Receptors
Glucocorticoid
Internal medicine
Glial Fibrillary Acidic Protein
medicine
Animals
Humans
Wobbler mice
Molecular Biology
CORTICOSTERONE
Aza Compounds
Dentate gyrus
Neuropeptides
Cell Biology
medicine.disease
Doublecortin
Disease Models
Animal
WOBBLER MICE
nervous system
CORT108297
Astrocytes
biology.protein
NeuN
Corticosterone
Zdroj: Journal of Steroid Biochemistry and Molecular Biology, 143, 40-48
ISSN: 0960-0760
DOI: 10.1016/j.jsbmb.2014.02.007
Popis: 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. Fil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Gonzalez Deniselle, Maria Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Hunt, Hazel. Corcept Therapeutics; Estados Unidos Fil: de Kloet, E. Ronald. Leiden University; Países Bajos Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Databáze: OpenAIRE
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