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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/6/2137 |
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| author | Alejandro F. De Nicola Maria Meyer Rachida Guennoun Michael Schumacher Hazel Hunt Joseph Belanoff E. Ronald de Kloet Maria Claudia Gonzalez Deniselle |
| author_facet | Alejandro F. De Nicola Maria Meyer Rachida Guennoun Michael Schumacher Hazel Hunt Joseph Belanoff E. Ronald de Kloet Maria Claudia Gonzalez Deniselle |
| author_sort | Alejandro F. De Nicola |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T09:57:04Z |
| format | Article |
| id | doaj.art-cca2ff2fdf69493cb08d64028c6f33eb |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-13T09:57:04Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cca2ff2fdf69493cb08d64028c6f33eb2022-12-22T02:51:21ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-03-01216213710.3390/ijms21062137ijms21062137Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative DiseasesAlejandro F. De Nicola0Maria Meyer1Rachida Guennoun2Michael Schumacher3Hazel Hunt4Joseph Belanoff5E. Ronald de Kloet6Maria Claudia Gonzalez Deniselle7Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, ArgentinaLaboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, ArgentinaU1195 Inserm and University Paris-Sud and University Paris Saclay 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, FranceU1195 Inserm and University Paris-Sud and University Paris Saclay 80 rue du Général Leclerc, 94276 Kremlin-Bicêtre, FranceCORCEPT Therapeutics, 149 Commonwealth Dr, Menlo Park, CA 94025, USACORCEPT Therapeutics, 149 Commonwealth Dr, Menlo Park, CA 94025, USADivision of Endocrinology, Dept. of Internal Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsLaboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina Experimental-CONICET, Obligado 2490, 1428 Buenos Aires, ArgentinaGlucocorticoids 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.https://www.mdpi.com/1422-0067/21/6/2137wobbler mouseamyotrophic lateral sclerosisglucocorticoid receptor antagonistneurodegenerationneuroinflammation |
| spellingShingle | Alejandro F. De Nicola Maria Meyer Rachida Guennoun Michael Schumacher Hazel Hunt Joseph Belanoff E. Ronald de Kloet Maria Claudia Gonzalez Deniselle Insights into the Therapeutic Potential of Glucocorticoid Receptor Modulators for Neurodegenerative Diseases International Journal of Molecular Sciences wobbler mouse amyotrophic lateral sclerosis glucocorticoid receptor antagonist neurodegeneration neuroinflammation |
| 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 | wobbler mouse amyotrophic lateral sclerosis glucocorticoid receptor antagonist neurodegeneration neuroinflammation |
| url | https://www.mdpi.com/1422-0067/21/6/2137 |
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