SUN-214 A Novel Glucocorticoid Receptor Antagonist (CORT113176) Reveals Unique Developmental and Tissue-Specific Effects in a Neonatal Rat Model of Human Prematurity

Premature birth is a major public health problem worldwide and can lead to transient adrenal insufficiency(1,2). The stress of premature birth includes the inability to control blood glucose and maintain normal oxygenation leading to hypoxia(3). Corticosteroid administration enhances surfactant production and improves oxygenation in preterm humans. However, corticosteroids can also have negative consequences(4,5). We have validated a rat model of separation and hypoxia on post-natal day (PD) 2 that emulates the stress and treatment of hypoxia in the preterm human infant(6,7). We hypothesized that the role of endogenous glucocorticoids in our neonatal rat model of preterm birth can be evaluated using the novel selective glucocorticoid receptor (GR) antagonist CORT113176 (Corcept) which is devoid of progesterone receptor effects(8). Pups (PD 2, 8, or 15; N=6–8 per treatment/timepoint) were given CORT113176 (60 mg/kg IP) or vehicle, then placed into chambers in room air with mild warming to prevent hypothermia due to maternal separation. 60 min later, one group of pups was euthanized and trunk blood collected (baseline). The remaining pups were exposed to hypoxia (8% O2) or normoxia (time control) for 30 or 60 min at which times trunk blood was collected for the measurement of plasma glucose, insulin, ACTH, and corticosterone. Plasma ACTH, corticosterone, and insulin were measured by immunoassay. Glucose was measured by glucose oxidase method and insulin sensitivity calculated (HOMA-IR). Organs were frozen (brain, pituitary, adrenal glands, kidney, liver, muscle, fat) for future assessment of tissue-specific glucocorticoid-sensitive gene expression. In PD2 rats, basal and hypoxia-stimulated plasma ACTH and corticosterone were lower and basal HOMA-IR greater with CORT113176 pretreatment suggesting (unexpectedly) glucocorticoid agonist activity. In PD8 and PD15 rats, basal and hypoxia-stimulated plasma ACTH and corticosterone were augmented after CORT113176 pretreatment demonstrating classic antagonist activity. However, in PD8 rats, CORT113176 effects were tissue-specific acting as a classic antagonist on the HPA-axis, but as an agonist on whole-body insulin resistance. The differential effects of CORT113176 based on age and target tissue indicate that GR regulation changes in early development in our animal model of human prematurity. These findings may have significant implications in the treatment of hypoxia and transient adrenal insufficiency in the preterm infant(1,2) as well as give insight into the nuances of the control of glucocorticoid receptor function. (1)Lancet 392:1923–1994, 2018 (2)Curr Opin Endocrinol Diabetes Obes 17:8–12, 2010 (3)Compr Ther 13:14–19, 1987 (4)Int Immunopharmacol 66:242–250, 2019 (5)J Neuroendocrinol 27:468–480, 2015 (6)Am J Physiol 300:R708-715, 2011 (7)Am J Physiol 302:R627-R633, 2012 (8)Med Chem Lett 25:5720−5725, 2015