Insights on Glucocorticoid Receptors’ Role in Drug-Resistant Epilepsy
Ongoing research is pursuing glucocorticoid receptors as a potential therapeutic target to overcome the role of blood-brain barrier dysfunction in pharmacoresistant epilepsy.
Glucocorticoid receptors (GRs) play a significant role in pharmacoresistant epilepsy and represent a potential therapeutic target, suggests an ongoing line of investigation by Cleveland Clinic researchers.
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“We believe that dysfunction of the blood-brain barrier (BBB) contributes to resistance to antiepileptic drug therapy in about 25 to 30 percent of epileptic patients with uncontrolled seizures,” says lead researcher Chaitali Ghosh, PhD, Staff Scientist in the Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, and Assistant Professor of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. “So we set out to examine how mechanistic regulation of glucocorticoid receptors in endothelial cells in the human epileptic brain could affect BBB properties. We also aimed to explore the relevance of glucocorticoid receptors to drug penetration across the BBB and to drug metabolism.”
The latest work by Dr. Ghosh’s group, which includes coinvestigators at Lerner Research Institute and clinical colleagues from Cleveland Clinic’s Epilepsy Center, builds on an earlier study by her team (Epilepsia. 2017;58:576-585) that focused on nuclear receptors — e.g., GRs and pregnane X receptors — involved in regulation of cytochrome P450 (CYP450) enzyme expression. They found that the nuclear receptors were co-expressed with CYP450 enzymes, which metabolize a number of medications, including antiepileptic drugs, and contribute to drug resistance in the human epileptic brain (Figure 1).
“We showed that endothelial cells isolated from postsurgical human brain specimens from patients with epilepsy overexpressed both glucocorticoid and pregnane X receptors — as well as CYP450 enzymes —relative to control brain endothelial cells,” Dr. Ghosh explains.
In their latest study (Epilepsia. 2018;59:2049-2060), the researchers found that by downregulating GR expression in endothelial cells of the BBB in human epileptic brain — either by GR silencing or by pharmacologic GR inhibition — they could reduce levels of CYP450 enzymes and drug-efflux transporters such as multidrug resistance protein 1 (MDR1) (Figure 2).
Using endothelial cells derived from surgically resected brain specimens from patients with pharmacoresistant epilepsy, the researchers recreated a physiologically relevant, flow-based in vitro BBB model for the study. They used the model to test silencing and inhibition of GRs, which diminished expression of pregnane X receptor, the CYP3A4 enzyme and MDR1.
The findings suggest that GR modulation in epileptic endothelial cells does several things, the investigators noted:
“This latest study indicates that glucocorticoid receptors may play a significant role in expression of pharmacoresistance in epilepsy by way of reduced drug bioavailability to epileptic brain areas,” Dr. Ghosh notes. “We showed that this role depends on downstream regulation of drug-metabolizing enzymes and efflux transporters in endothelial cells at the BBB. This work paves the way toward consideration of the glucocorticoid receptor as a therapeutic target in the endothelium to influence brain vasculature in a way that overcomes the pharmacokinetics behind resistance to antiepileptic medications.”