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Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases
Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139912/ https://www.ncbi.nlm.nih.gov/pubmed/32244957 http://dx.doi.org/10.3390/ijms21062137 |
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author | De Nicola, Alejandro F. Meyer, Maria Guennoun, Rachida Schumacher, Michael Hunt, Hazel Belanoff, Joseph de Kloet, E. Ronald Gonzalez Deniselle, Maria Claudia |
author_facet | De Nicola, Alejandro F. Meyer, Maria Guennoun, Rachida Schumacher, Michael Hunt, Hazel Belanoff, Joseph de Kloet, E. Ronald Gonzalez Deniselle, Maria Claudia |
author_sort | De Nicola, Alejandro F. |
collection | PubMed |
description | Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic–pituitary–adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine–threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-7139912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71399122020-04-13 Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases De Nicola, Alejandro F. Meyer, Maria Guennoun, Rachida Schumacher, Michael Hunt, Hazel Belanoff, Joseph de Kloet, E. Ronald Gonzalez Deniselle, Maria Claudia Int J Mol Sci Review Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic–pituitary–adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine–threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases. MDPI 2020-03-20 /pmc/articles/PMC7139912/ /pubmed/32244957 http://dx.doi.org/10.3390/ijms21062137 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review De Nicola, Alejandro F. Meyer, Maria Guennoun, Rachida Schumacher, Michael Hunt, Hazel Belanoff, Joseph de Kloet, E. Ronald Gonzalez Deniselle, Maria Claudia Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases |
title | Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases |
title_full | Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases |
title_fullStr | Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases |
title_full_unstemmed | Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases |
title_short | Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases |
title_sort | insights into the therapeutic potential of glucocorticoid receptor modulators for neurodegenerative diseases |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139912/ https://www.ncbi.nlm.nih.gov/pubmed/32244957 http://dx.doi.org/10.3390/ijms21062137 |
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