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

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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 glucocorticoi...

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Autor principal: Meyer, M.
Otros Autores: Gonzalez Deniselle, M.C, Hunt, H., Kloet, E.R.D, De Nicola, A.F
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Lenguaje:Inglés
Publicado: Elsevier Ltd 2014
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cort 108297
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024 7 |2 cas  |a 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 
040 |a Scopus  |b spa  |c AR-BaUEN  |d AR-BaUEN 
030 |a JSBBE 
100 1 |a Meyer, M. 
245 1 4 |a The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice 
260 |b Elsevier Ltd  |c 2014 
270 1 0 |m De Nicola, A.F.; Instituto de Biologia y Medicina Experimental, Laboratort of Neuroendocrine Biochemistry, Obligado 2490, 1428 Buenos Aires, Argentina; email: alejandrodenicola@gmail.com 
506 |2 openaire  |e Política editorial 
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520 3 |a 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.  |l eng 
536 |a Detalles de la financiación: Universidad de Buenos Aires, Ubacyt 20020100100089 
536 |a Detalles de la financiación: Fundación Alberto J. Roemmers 
536 |a Detalles de la financiación: Fundación Florencio Fiorini 
536 |a Detalles de la financiación: Consejo Nacional de Investigaciones Científicas y Técnicas, PIP-112201201-00016 
536 |a Detalles de la financiación: Ministry of Science and Technology, PICT 2012-0009 
536 |a Detalles de la financiación: This work was supported by grants from the Ministry of Science and Technology ( PICT 2012-0009 ) CONICET ( PIP-112201201-00016 ), the University of Buenos Aires ( Ubacyt 20020100100089 ) and Fundación Roemmers . Dr. Maria Meyer was supported by Fundación Bunge & Born and Fundación Florencio Fiorini. These findings sources had no role in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. 
593 |a Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y Medicina Experimental, CONICET, Obligado 2490, 1428 Buenos Aires, Argentina 
593 |a Dept. of Human Biochemistry, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1425 Buenos Aires, Argentina 
593 |a Corcept Therapeutics, 149 Commonwealth Drive, Menlo Park, CA 94025, United States 
593 |a LACDR/LUMC, Leiden University, Einstein weg 55, 2333 CC Leiden, Netherlands 
690 1 0 |a ASTROGLIOSIS 
690 1 0 |a CORT108297 
690 1 0 |a CORTICOSTERONE 
690 1 0 |a GLUCOCORTICOID RECEPTOR ANTAGONIST 
690 1 0 |a HIPPOCAMPUS 
690 1 0 |a MICROGLIA 
690 1 0 |a NEUROGENESIS 
690 1 0 |a WOBBLER MICE 
690 1 0 |a BINDING PROTEIN 
690 1 0 |a BRAIN PROTEIN 
690 1 0 |a CORT 108297 
690 1 0 |a CORT108297 
690 1 0 |a CORTICOSTERONE 
690 1 0 |a DOUBLECORTIN 
690 1 0 |a GLIAL FIBRILLARY ACIDIC PROTEIN 
690 1 0 |a GLUCOCORTICOID RECEPTOR 
690 1 0 |a IONIZED CALCIUM BINDING ADAPTER MOLECULE 1 
690 1 0 |a NEURON SPECIFIC NUCLEAR PROTEIN 
690 1 0 |a RECOMBINANT HORMONE 
690 1 0 |a UNCLASSIFIED DRUG 
690 1 0 |a ANTIINFLAMMATORY AGENT 
690 1 0 |a CORT 108297 
690 1 0 |a CORTICOSTERONE 
690 1 0 |a DOUBLECORTIN PROTEIN 
690 1 0 |a FUSED HETEROCYCLIC RINGS 
690 1 0 |a GLIAL FIBRILLARY ACIDIC PROTEIN 
690 1 0 |a GLUCOCORTICOID RECEPTOR 
690 1 0 |a HETEROCYCLIC COMPOUND 
690 1 0 |a MICROTUBULE ASSOCIATED PROTEIN 
690 1 0 |a NERVE PROTEIN 
690 1 0 |a NEUN PROTEIN, MOUSE 
690 1 0 |a NEUROPEPTIDE 
690 1 0 |a NUCLEAR PROTEIN 
690 1 0 |a ADRENAL CORTEX DISEASE 
690 1 0 |a ANIMAL EXPERIMENT 
690 1 0 |a ANIMAL MODEL 
690 1 0 |a ARTICLE 
690 1 0 |a ASTROCYTE 
690 1 0 |a ASTROCYTE HYPERTROPHY 
690 1 0 |a ASTROCYTOSIS 
690 1 0 |a CELL ACTIVITY 
690 1 0 |a CELL COUNT 
690 1 0 |a CELL FUNCTION 
690 1 0 |a CONTROLLED STUDY 
690 1 0 |a CORTICOSTERONE BLOOD LEVEL 
690 1 0 |a DENTATE GYRUS 
690 1 0 |a DOUBLECORTIN+ NEUROBLAST 
690 1 0 |a DRUG BRAIN LEVEL 
690 1 0 |a DRUG EFFECT 
690 1 0 |a DRUG MECHANISM 
690 1 0 |a DRUG RECEPTOR BINDING 
690 1 0 |a DRUG RESPONSE 
690 1 0 |a GLIAL FIBRILLARY ACIDIC PROTEIN+ASTROCYTE 
690 1 0 |a HIPPOCAMPUS 
690 1 0 |a HYPERCORTICOSTERONEMIA 
690 1 0 |a HYPERTROPHY 
690 1 0 |a IONIZED CALCIUM BINDING ADAPTER MOLECULE 1+MICROGLIA 
690 1 0 |a MICROGLIA 
690 1 0 |a MOUSE 
690 1 0 |a NERVOUS SYSTEM PARAMETERS 
690 1 0 |a NEUROBLAST 
690 1 0 |a NEURON SPECIFIC NUCLEAR PROTEIN+ CELL 
690 1 0 |a NONHUMAN 
690 1 0 |a PHENOTYPE 
690 1 0 |a TREATMENT DURATION 
690 1 0 |a ANIMAL 
690 1 0 |a ANTAGONISTS AND INHIBITORS 
690 1 0 |a CELL CULTURE 
690 1 0 |a COMPARATIVE STUDY 
690 1 0 |a CYTOLOGY 
690 1 0 |a DISEASE MODEL 
690 1 0 |a DRUG EFFECTS 
690 1 0 |a ENZYME IMMUNOASSAY 
690 1 0 |a FEMALE 
690 1 0 |a FLUORESCENT ANTIBODY TECHNIQUE 
690 1 0 |a HIPPOCAMPUS 
690 1 0 |a HUMAN 
690 1 0 |a METABOLISM 
690 1 0 |a MOUSE MUTANT 
690 1 0 |a NERVE CELL 
690 1 0 |a PHYSIOLOGY 
690 1 0 |a WESTERN BLOTTING 
690 1 0 |a ANIMALS 
690 1 0 |a ANTI-INFLAMMATORY AGENTS 
690 1 0 |a ASTROCYTES 
690 1 0 |a AZA COMPOUNDS 
690 1 0 |a BLOTTING, WESTERN 
690 1 0 |a CELLS, CULTURED 
690 1 0 |a CORTICOSTERONE 
690 1 0 |a DISEASE MODELS, ANIMAL 
690 1 0 |a FEMALE 
690 1 0 |a FLUORESCENT ANTIBODY TECHNIQUE 
690 1 0 |a GLIAL FIBRILLARY ACIDIC PROTEIN 
690 1 0 |a HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS 
690 1 0 |a HIPPOCAMPUS 
690 1 0 |a HUMANS 
690 1 0 |a IMMUNOENZYME TECHNIQUES 
690 1 0 |a MICE 
690 1 0 |a MICE, NEUROLOGIC MUTANTS 
690 1 0 |a MICROGLIA 
690 1 0 |a MICROTUBULE-ASSOCIATED PROTEINS 
690 1 0 |a NERVE TISSUE PROTEINS 
690 1 0 |a NEURONS 
690 1 0 |a NEUROPEPTIDES 
690 1 0 |a NUCLEAR PROTEINS 
690 1 0 |a RECEPTORS, GLUCOCORTICOID 
653 0 0 |a cort 108297 
700 1 |a Gonzalez Deniselle, M.C. 
700 1 |a Hunt, H. 
700 1 |a Kloet, E.R.D. 
700 1 |a De Nicola, A.F. 
773 0 |d Elsevier Ltd, 2014  |g v. 143  |h pp. 40-48  |p J. Steroid Biochem. Mol. Biol.  |x 09600760  |w (AR-BaUEN)CENRE-5799  |t Journal of Steroid Biochemistry and Molecular Biology 
856 4 1 |u https://www.scopus.com/inward/record.uri?eid=2-s2.0-84896124043&doi=10.1016%2fj.jsbmb.2014.02.007&partnerID=40&md5=a4e7c0a454cf0301c6ed545e24eb9be2  |y Registro en Scopus 
856 4 0 |u https://doi.org/10.1016/j.jsbmb.2014.02.007  |y DOI 
856 4 0 |u https://hdl.handle.net/20.500.12110/paper_09600760_v143_n_p40_Meyer  |y Handle 
856 4 0 |u https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v143_n_p40_Meyer  |y Registro en la Biblioteca Digital 
961 |a paper_09600760_v143_n_p40_Meyer  |b paper  |c PE 
962 |a info:eu-repo/semantics/article  |a info:ar-repo/semantics/artículo  |b info:eu-repo/semantics/publishedVersion 
999 |c 85011 

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