Neuropathological Effects of Early Maternal Separation are Prevented by CORT113176, A Glucocorticoid Receptor Modulator

Abstract

Early-life stress, such as maternal separation (MS), disrupts the pup´s hypothalamic–pituitary–adrenal (HPA) axis and causes neuropathological changes in several nervous system regions, including the spinal cord. This damage is driven by glucocorticoid receptor (GR) overactivation, which triggers neuroinflammation by dysfunctional changes in glial and neuronal cells. This study evaluated whether CORT113176 (dazucorilant)—a highly selective GR modulator— prevented the development of neuropathology in a murine model of repeated MS. Postnatal day 2 (PND2) NFR/NFR mice were assigned to three groups: control, MS (3-h daily maternal separation from PND2 to PND12 + vehicle), and MS + CORT113176 (30 mg/kg s.c. every other day). CORT113176 administration significantly mitigated the abnormalities effects of postnatal stress in the spinal cord. The selective GR modulator successfully: 1- decreased reactive astrogliosis and microglial activation markers (GFAP, GS, IBA1). 2- attenuated the expression of pro-inflammatory and stress-response genes. 3- protected neurons from stress-induced decreased BDNF and NeuN markers and 4- rescued myelin-producing cells and the water channel aquaporin-4 thus, pharmacological modulation of the GR with CORT113176 effectively intercepts the harmful neuroinflammatory and degenerative pathways triggered by early adverse experiences. These data provide robust evidence that selective GR inhibition is a viable therapeutic strategy against the pup’s neurological consequences of maternal separation.