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: Maria Meyer, Maria Claudia Gonzalez Deniselle, Hazel Hunt, E Ronald de Kloet, Alejandro F De Nicola
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 143 Pg. 40-8 (Sep 2014) ISSN: 1879-1220 [Electronic] England
• PMID: 24565565 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Aza Compounds
• CORT 108297
• DCX protein, human
• DNA-Binding Proteins
• Dcx protein, mouse
• Doublecortin Domain Proteins
• Doublecortin Protein
• Glial Fibrillary Acidic Protein
• Heterocyclic Compounds, 4 or More Rings
• Microtubule-Associated Proteins
• Nerve Tissue Proteins
• NeuN protein, mouse
• Neuropeptides
• Nuclear Proteins
• Receptors, Glucocorticoid
• Corticosterone

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Astrocytes (cytology, drug effects, metabolism)
• Aza Compounds (pharmacology)
• Blotting, Western
• Cells, Cultured
• Corticosterone (pharmacology)
• DNA-Binding Proteins
• Disease Models, Animal
• Doublecortin Domain Proteins
• Doublecortin Protein
• Female
• Fluorescent Antibody Technique
• Glial Fibrillary Acidic Protein (metabolism)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Hippocampus (abnormalities, drug effects, metabolism)
• Humans
• Immunoenzyme Techniques
• Mice
• Mice, Neurologic Mutants
• Microglia (cytology, drug effects, metabolism)
• Microtubule-Associated Proteins (physiology)
• Nerve Tissue Proteins (metabolism)
• Neurons (cytology, drug effects, metabolism)
• Neuropeptides (physiology)
• Nuclear Proteins (metabolism)
• Receptors, Glucocorticoid (antagonists & inhibitors, metabolism)