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Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator
Open accessAbstract
Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus–pituitary–adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling.
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“inhibiting other GR-mediated effects such as the negative feedback on the HPA axis could lead to increased cortisol levels, which could in turn, activate mineralocorticoid receptors (Zalachoras et al., 2013) and modulate alcohol dependence-related behaviors (Aoun et al., 2018).”
From Alcohol dependence and withdrawal increase sensitivity of central amygdalar GABAergic synapses to the glucocorticoid receptor antagonist mifepristone in male rats (2022) · cites this paper as Zalachoras et al., 2013
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Metadata
- Authors
- Zalachoras, I., Houtman, R., Atucha, E., Devos, R., Tijssen, A. M. I., Hu, P., Lockey, P. M., Datson, N. A., Belanoff, J. K., Lucassen, P. J., Joëls, M., de Kloet, E. R., Roozendaal, B., Hunt, H., & Meijer, O. C.
- Affiliations
- Leiden University Medical Center (NL)
- PamGene (Netherlands) (NL)
- Radboud University Nijmegen (NL)
- Argenta Discovery, Harlow, Essex CM19 5TR, United Kingdom;
- Division Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands;
- University of Amsterdam (NL)
- Corcept Therapeutics (United States) (US)
- University Medical Center Utrecht (NL)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-04-23
- Volume
- 110
- Issue
- 19
- Pages
- 7910-7915
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3651427
- OpenAlex
- W2161618887
- Cited by
- 121
- References
- 50
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 6 · 2020: 4 · 2019: 15 · 2018: 15 · 2017: 10 · 2016: 16 · 2015: 8 · 2014: 9 · 2013: 7
- FWCI
- 6.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- glucocorticoid receptor, selective glucocorticoid receptor modulators, depression, corticotropin-releasing factor, hypothalamus, central amygdala, hippocampal neurogenesis, hypothalamic-pituitary-adrenal axis, nuclear receptor coregulators, dexamethasone, mifepristone, chronic corticosterone
- MeSH terms
- Animals, Brain, Corticotropin-Releasing Hormone, Dexamethasone, Gene Expression Regulation, Hippocampus, Ligands, Male, Peptides, Receptors, Glucocorticoid, Steroids, Time Factors, Transcription, Genetic, Mifepristone, Rats, Sprague-Dawley, Two-Hybrid System Techniques, Rats, Nuclear Receptor Coactivator 1
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