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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. © 2014 Elsevier Ltd.

Registro:

Documento: Artículo
Título:The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice
Autor:Meyer, M.; Gonzalez Deniselle, M.C.; Hunt, H.; Kloet, E.R.D.; De Nicola, A.F.
Filiación: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
Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, United States
LACDR/LUMC, Leiden University, Einstein weg 55, 2333 CC Leiden, Netherlands
Palabras clave:Astrogliosis; CORT108297; Corticosterone; Glucocorticoid receptor antagonist; Hippocampus; Microglia; Neurogenesis; Wobbler mice; binding protein; brain protein; cort 108297; cort108297; corticosterone; doublecortin; glial fibrillary acidic protein; glucocorticoid receptor; ionized calcium binding adapter molecule 1; neuron specific nuclear protein; recombinant hormone; unclassified drug; antiinflammatory agent; CORT 108297; corticosterone; doublecortin protein; fused heterocyclic rings; glial fibrillary acidic protein; glucocorticoid receptor; heterocyclic compound; microtubule associated protein; nerve protein; NeuN protein, mouse; neuropeptide; nuclear protein; adrenal cortex disease; animal experiment; animal model; article; astrocyte; astrocyte hypertrophy; astrocytosis; cell activity; cell count; cell function; controlled study; corticosterone blood level; dentate gyrus; doublecortin+ neuroblast; drug brain level; drug effect; drug mechanism; drug receptor binding; drug response; glial fibrillary acidic protein+astrocyte; hippocampus; hypercorticosteronemia; hypertrophy; ionized calcium binding adapter molecule 1+microglia; microglia; mouse; nervous system parameters; neuroblast; neuron specific nuclear protein+ cell; nonhuman; phenotype; treatment duration; animal; antagonists and inhibitors; cell culture; comparative study; cytology; disease model; drug effects; enzyme immunoassay; female; fluorescent antibody technique; hippocampus; human; metabolism; mouse mutant; nerve cell; physiology; Western blotting; Animals; Anti-Inflammatory Agents; Astrocytes; Aza Compounds; Blotting, Western; Cells, Cultured; Corticosterone; Disease Models, Animal; Female; Fluorescent Antibody Technique; Glial Fibrillary Acidic Protein; Heterocyclic Compounds with 4 or More Rings; Hippocampus; Humans; Immunoenzyme Techniques; Mice; Mice, Neurologic Mutants; Microglia; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neurons; Neuropeptides; Nuclear Proteins; Receptors, Glucocorticoid
Año:2014
Volumen:143
Página de inicio:40
Página de fin:48
DOI: http://dx.doi.org/10.1016/j.jsbmb.2014.02.007
Título revista:Journal of Steroid Biochemistry and Molecular Biology
Título revista abreviado:J. Steroid Biochem. Mol. Biol.
ISSN:09600760
CODEN:JSBBE
CAS:corticosterone, 50-22-6; doublecortin, 202938-39-4; Anti-Inflammatory Agents; Aza Compounds; CORT 108297; Corticosterone; doublecortin protein; Glial Fibrillary Acidic Protein; Heterocyclic Compounds with 4 or More Rings; Microtubule-Associated Proteins; Nerve Tissue Proteins; NeuN protein, mouse; Neuropeptides; Nuclear Proteins; Receptors, Glucocorticoid
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v143_n_p40_Meyer

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Citas:

---------- APA ----------
Meyer, M., Gonzalez Deniselle, M.C., Hunt, H., Kloet, E.R.D. & De Nicola, A.F. (2014) . The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice. Journal of Steroid Biochemistry and Molecular Biology, 143, 40-48.
http://dx.doi.org/10.1016/j.jsbmb.2014.02.007
---------- CHICAGO ----------
Meyer, M., Gonzalez Deniselle, M.C., Hunt, H., Kloet, E.R.D., De Nicola, A.F. "The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice" . Journal of Steroid Biochemistry and Molecular Biology 143 (2014) : 40-48.
http://dx.doi.org/10.1016/j.jsbmb.2014.02.007
---------- MLA ----------
Meyer, M., Gonzalez Deniselle, M.C., Hunt, H., Kloet, E.R.D., De Nicola, A.F. "The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice" . Journal of Steroid Biochemistry and Molecular Biology, vol. 143, 2014, pp. 40-48.
http://dx.doi.org/10.1016/j.jsbmb.2014.02.007
---------- VANCOUVER ----------
Meyer, M., Gonzalez Deniselle, M.C., Hunt, H., Kloet, E.R.D., De Nicola, A.F. The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice. J. Steroid Biochem. Mol. Biol. 2014;143:40-48.
http://dx.doi.org/10.1016/j.jsbmb.2014.02.007