The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity.

Lisa L Koorneef,Menno Hoekstra,Kim M L Heckmans,Lucas F Wahl,Marloes M A R Van Dorst,Jan Kroon,Hazel Hunt,Eva M G Viho,René Houtman,Onno C Meijer

doi:10.1530/joe-19-0486

Abstract

Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.

Highlights

Glucocorticoids (GCs) are adrenal hormones involved in the stress response, regulating processes such as immune function and metabolism
Using RT-qPCR, we analyzed in several tissues expression levels of four general and well-established glucocorticoid receptor (GR) target genes: FK506-binding protein 51 (Fkbp5), glucocorticoid-induced leucine zipper (Gilz/Tsc22d3), Serum/Glucocorticoid Regulated Kinase 1 (Sgk1) and Metallothionein 2 (Mt2a)
We investigated the efficacy of the selective GR antagonist CORT125281 across several doses in various GC-sensitive tissues during acute and subchronic corticosterone exposure

Summary

Introduction

Glucocorticoids (GCs) are adrenal hormones involved in the stress response, regulating processes such as immune function and metabolism. The hypothalamus-pituitaryadrenal (HPA)-axis controls GC secretion via a cascade of hormonal events: corticotrophin-releasing hormone from the hypothalamic paraventricular nucleus (PVN). 246:1 induces adrenocorticotropic hormone (ACTH) release by the anterior pituitary, thereby triggering GC production and secretion by the adrenals (Herman et al 2016). The most widely expressed GC receptor is the glucocorticoid receptor (GR), which mediates many effects on target tissues while simultaneously dampening HPA-axis activity via negative feedback loops at the level of the pituitary and the PVN. Given the pleiotropic nature of GR signaling, excessive HPA-axis activity is accompanied by disease, as exemplified by patients with Cushing’s syndrome (Ferrau & Korbonits 2015). The classic GR antagonist mifepristone (RU486) is commonly used to treat these patients (CuevasRamos et al 2016). Mifepristone is often applied to experimentally manipulate GR activity. There is a need for more selective GR antagonists

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