Glucocorticoid Receptor beta Isoform Predominates in the Human Dysplastic Brain Region and Is Modulated by Age, Sex, and Antiseizure Medication

The glucocorticoid receptor (GR) at the blood-brain barrier (BBB) is involved in the pathogenesis of drug-resistant epilepsy with focal cortical dysplasia (FCD); however, the roles of GR isoforms GR alpha and GR beta in the dysplastic brain have not been revealed. We utilized dysplastic/epileptic and non-dysplastic brain tissue from patients who underwent resective epilepsy surgery to identify the GR alpha and GR beta levels, subcellular localization, and cellular specificity. BBB endothelial cells isolated from the dysplastic brain tissue (EPI-ECs) were used to decipher the key BBB proteins related to drug regulation and BBB integrity compared to control and transfected GR beta-overexpressed BBB endothelial cells. GR beta was upregulated in dysplastic compared to non-dysplastic tissues, and an imbalance of the GR alpha/GR beta ratio was significant in females vs. males and in patients > 45 years old. In EPI-ECs, the subcellular localization and expression patterns of GR beta, Hsp90, CYP3A4, and CYP2C9 were consistent with GR beta+ brain endothelial cells. Active matrix metalloproteinase levels and activity increased, whereas claudin-5 levels decreased in both EPI-ECs and GR beta+ endothelial cells. In conclusion, the GR beta has a major effect on dysplastic BBB functional proteins and is age and gender-dependent, suggesting a critical role of brain GR beta in dysplasia as a potential biomarker and therapeutic target in epilepsy.