Mineralocorticoid receptor excessive activation involved in glucocorticoid-related brain injury

The mechanisms involved in brain damage during chronic glucocorticoid exposure are poorly understood. Since mineralocorticoid receptor (MR) activation has been proven to be important in the pathophysiology of vascular damage and MRs are highly expressed in many brain regions, we hypothesized that the cerebral injury observed in subjects with Cushing syndrome is in part associated with the overactivation of MR. The aim of this study was to determine whether the cerebral injury observed in chronic hyperglucocorticoidemia animal models is related to excessive MR activation. Male SD rats were divided into five groups: vehicle, hydrocortisone (HC, 5 mg/kg/day, i.g.), HC + spironolactone (SL, 20 mg/kg/d in chow), dexamethasone (DXM, 0.25 mg/kg/day, i.g.), and DXM + SL (20 mg/kg/d in chow). Compared to the vehicle-treated group, HC-treated rats had higher blood pressure and higher levels of cerebral vascular fibrosis, cortical/hippocampal atrophy, reactive oxygen species (ROS) production and proinflammatory gene expression. However, in HC-treated animals, treatment with SL markedly alleviated ROS production, cerebral and cerebrovascular morphological changes and inflammation but failed to reduce blood pressure. In contrast, DXM induced no cerebral morphological changes except fibrosis in cerebral vessels, an effect that was not ameliorated by SL treatment. These findings demonstrate that the excessive MR activation observed following chronic hyperglucocorticoidemia exposure contributes to cerebrovascular fibrosis and remodeling and promotes neural apoptosis in the cerebral cortex/hippocampus.