Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases

Autores
de Nicola, Alejandro Federico; Meyer, Maria; Guennoun, Rachida; Schumacher, Michael; Hunt, Hazel; Belanoff, Joseph; de Kloet, E. Ronald; Gonzalez Deniselle, Maria Claudia
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Fil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Guennoun, Rachida. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; Francia
Fil: Schumacher, Michael. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; Francia
Fil: Hunt, Hazel. Corcepts Therapeutics; Estados Unidos
Fil: Belanoff, Joseph. Corcepts Therapeutics; Estados Unidos
Fil: de Kloet, E. Ronald. Leiden University. Leiden University Medical Center.; Países Bajos
Fil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Materia
ALS
GLUCOCORTICOIDS
ANTIGLUCOCORTICOID
WOBBLER
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/111349
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/111349
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseasesde Nicola, Alejandro FedericoMeyer, MariaGuennoun, RachidaSchumacher, MichaelHunt, HazelBelanoff, Josephde Kloet, E. RonaldGonzalez Deniselle, Maria ClaudiaALSGLUCOCORTICOIDSANTIGLUCOCORTICOIDWOBBLERhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Glucocorticoids 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.Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Guennoun, Rachida. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; FranciaFil: Schumacher, Michael. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; FranciaFil: Hunt, Hazel. Corcepts Therapeutics; Estados UnidosFil: Belanoff, Joseph. Corcepts Therapeutics; Estados UnidosFil: de Kloet, E. Ronald. Leiden University. Leiden University Medical Center.; Países BajosFil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaMolecular Diversity Preservation International2020-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/111349de Nicola, Alejandro Federico; Meyer, Maria; Guennoun, Rachida; Schumacher, Michael; Hunt, Hazel; et al.; Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 21; 3-2020; 1-161422-0067CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139912/info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21062137info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:00:40Zoai:ri.conicet.gov.ar:11336/111349instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:00:40.93CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 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
spellingShingle Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases
de Nicola, Alejandro Federico
ALS
GLUCOCORTICOIDS
ANTIGLUCOCORTICOID
WOBBLER
title_short 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_sort Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases
dc.creator.none.fl_str_mv de Nicola, Alejandro Federico
Meyer, Maria
Guennoun, Rachida
Schumacher, Michael
Hunt, Hazel
Belanoff, Joseph
de Kloet, E. Ronald
Gonzalez Deniselle, Maria Claudia
author de Nicola, Alejandro Federico
author_facet de Nicola, Alejandro Federico
Meyer, Maria
Guennoun, Rachida
Schumacher, Michael
Hunt, Hazel
Belanoff, Joseph
de Kloet, E. Ronald
Gonzalez Deniselle, Maria Claudia
author_role author
author2 Meyer, Maria
Guennoun, Rachida
Schumacher, Michael
Hunt, Hazel
Belanoff, Joseph
de Kloet, E. Ronald
Gonzalez Deniselle, Maria Claudia
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALS
GLUCOCORTICOIDS
ANTIGLUCOCORTICOID
WOBBLER
topic ALS
GLUCOCORTICOIDS
ANTIGLUCOCORTICOID
WOBBLER
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Fil: Meyer, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Guennoun, Rachida. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; Francia
Fil: Schumacher, Michael. Inserm; Francia. Université Paris Sud; Francia. Université Paris Saclay; Francia
Fil: Hunt, Hazel. Corcepts Therapeutics; Estados Unidos
Fil: Belanoff, Joseph. Corcepts Therapeutics; Estados Unidos
Fil: de Kloet, E. Ronald. Leiden University. Leiden University Medical Center.; Países Bajos
Fil: Gonzalez Deniselle, Maria Claudia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
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.
publishDate 2020
dc.date.none.fl_str_mv 2020-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/111349
de Nicola, Alejandro Federico; Meyer, Maria; Guennoun, Rachida; Schumacher, Michael; Hunt, Hazel; et al.; Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 21; 3-2020; 1-16
1422-0067
CONICET Digital
CONICET
url http://hdl.handle.net/11336/111349
identifier_str_mv de Nicola, Alejandro Federico; Meyer, Maria; Guennoun, Rachida; Schumacher, Michael; Hunt, Hazel; et al.; Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases; Molecular Diversity Preservation International; International Journal of Molecular Sciences; 21; 3-2020; 1-16
1422-0067
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139912/
info:eu-repo/semantics/altIdentifier/doi/10.3390/ijms21062137
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Molecular Diversity Preservation International
publisher.none.fl_str_mv Molecular Diversity Preservation International
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.13397

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