Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: De Nicola, Alejandro F., Meyer, Maria, Guennoun, Rachida, Schumacher, Michael, Hunt, Hazel, Belanoff, Joseph, de Kloet, E. Ronald, Gonzalez Deniselle, Maria Claudia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783518875441168384
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
work_keys_str_mv AT denicolaalejandrof insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT meyermaria insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT guennounrachida insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT schumachermichael insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT hunthazel insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT belanoffjoseph insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT dekloeteronald insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases
AT gonzalezdenisellemariaclaudia insightsintothetherapeuticpotentialofglucocorticoidreceptormodulatorsforneurodegenerativediseases