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Insights on Glucocorticoid Receptors’ Role in Drug-Resistant Epilepsy

03/13/2019

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.

“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, Department of Biomedical Engineering. “So we set out to examine how mechanistic regulation of GRs in endothelial cells in the human epileptic brain could affect BBB receptors. We also aimed to explore the relevance of GRs to drug penetration across the BBB and to drug metabolism.”

Building on a link to CYP450 metabolism

The latest work by Dr. Ghosh’s group, which includes clinical colleagues from Cleveland Clinic’s Epilepsy Center, builds on an earlier study by her team that focused on nuclear receptors (including 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.

“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.

Exploring effects of GR downregulation

In their latest study, the researchers found that by downregulating GR expression in endothelial cells of the BBB in the human epileptic brain, either by GR silencing or pharmacologic GR inhibition, they could reduce levels of CYP450 enzymes and drug-efflux transporters such as multidrug resistance protein 1 (MDR1).

Using endothelial cells derived from surgically resected brain specimens from patients with pharmacoresistant epilepsy, the researchers created a physiologically relevant, flow-based in vitro BBB model for the study. The used the model to test silencing and inhibiting 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, including:

  • Increases the permeability of antiepileptic drugs such as phenytoin across the BBB
  • Reduces CYP450 metabolic function
  • Improves bioavailability of the antiepileptic drug oxcarbazepine to the brain side of the BBB by limiting drug breakdown at the BBB endothelium

A potential therapeutic target

“This latest study indicates that GRs 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 GR as a therapeutic target in the endothelium to influence brain vasculature in a way that overcomes the pharmacokinetics behind resistance to antiepileptic medications.”

Dr. Ghosh is also Assistant Professor of Molecular Medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

This story is adapted from Consult QD.



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