Inhibiting glucocorticoid receptors enhances adult spinal cord neural stem cell activity and improves outcomes in spinal cord injury.

The spinal cord injury (SCI) microenvironment undergoes significant biochemical changes that influence the behavior of endogenous neural stem/progenitor cells (NSPCs), including elevated glucocorticoid levels. Here, we investigate the effects of glucocorticoids on NSPCs in the adult mouse spinal cord. Adult spinal cord NSPCs express glucocorticoid receptors but not mineralocorticoid receptors. Glucocorticoid exposure significantly inhibits NSPC proliferation, neurosphere formation, and differentiation through glucocorticoid receptor activation. In a traumatic SCI mouse model, treatment with the glucocorticoid receptor inhibitor CORT125281 improves motor function and increases the number of NSPCs at the injury site. Flow cytometry and RNA sequencing analyses show that glucocorticoids induce NSPC G0/G1 cell-cycle arrest through activation of the p53 signaling pathway, accompanied by increased expression of the cell-cycle regulators p15, p18, and p27. These findings suggest that glucocorticoid elevation after SCI suppresses endogenous NSPC proliferation via glucocorticoid receptor activation, and targeting this pathway may represent a potential therapeutic strategy to enhance recovery after SCI.