Potential Target Discovered for Reversing Drug Resistance in Epilepsy

Dr. Ghosh’s team has learned about an important relationship between the glucocorticoid receptor and heat shock proteins, which may have clinical implications for treating patients who have drug-resistant epilepsy.

11/04/2020

Drug treatment is usually successful in controlling epilepsy. However, a significant percentage of patients—up to one-third of adults and one-quarter of children, according to the International League Against Epilepsy and the Epilepsy Foundation—have epilepsy that is drug-resistant, or pharmacoresistant. Specifically, this means that patients continue to experience seizures despite taking medications.

According to study findings published in Molecular Neurobiology, researchers in the Department of Biomedical Engineering, led by Chaitali Ghosh, PhD, discovered that the interaction between the glucocorticoid receptor (GR) and heat shock proteins may play a critical role in driving pharmacoresistant epilepsy.

They report that when GR is overexpressed, it binds with heat shock proteins—a family of proteins that help “chaperone” and keep order over other proteins—and co-localizes in the brain’s network of blood vessels and neurons. This co-localization and its downstream effects on other molecules, like enzymes and transporters, may prevent medications from reaching the targeted epileptic brain region, including crossing the blood-brain barrier, and so may contribute to pharmacoresistance.

As epilepsy develops, certain changes in the brain affect the way antiseizure medications work. The GR is an important target that plays a key role in regulating metabolic functions. At this time, however, the role of GR in epilepsy, particularly in the context of drug regulation at the blood-brain barrier, is not completely understood—leading to speculation that it may contribute to pharmacoresistance in a significant proportion of patients who have epilepsy.

Relationship between GR and heat shock proteins

The current study was designed to learn the mechanisms of GR-dependent drug resistance. “The coordinated action of protein chaperones enhances GR functioning in human epileptic tissues and epileptic brain endothelial cells derived from the resected tissue regions,” said Dr. Ghosh. “We believe that studying GR and heat shock protein interactions with chaperones or co-chaperones in dysplastic versus non-dysplastic regions of the same brain is a novel approach to determine intracellular mechanisms that contribute to epilepsy pathology.”

The researchers studied brain tissue from patients with pharmacoresistant epilepsy who underwent resective surgery. They found that GR protein activation was higher in specific dysplastic (epileptic) regions of the brain than it was in non-dysplastic (non-epileptic) regions.

Clinical considerations for patients with epilepsy

“We have learned in this study that in epileptic brain regions, the GR/heat shock protein regulatory mechanism may help amplify the activity of various proteins and enzymes that hinder drug delivery to the brain across blood-brain barrier endothelial cells,” noted Dr. Ghosh, “which, in turn, can facilitate pharmacoresistance.”

“This ongoing study is especially important for clinicians who are treating patients with drug-resistant epilepsy,” added Dr. Ghosh. “It points out the effects of GR modulation at the blood-brain barrier, which can influence decisions on which medications to prescribe for better drug bioavailability to the brain.”

This project was supported in part by the National Institute of Neurological Disorders and Stroke and the National Heart, Lung, and Blood Institute, both parts of the National Institutes of Health. Mohammed Hossain, a senior research technologist, and Sherice Williams, a research student in Dr. Ghosh’s lab, were co-first authors of the study.

Image: Histological characterization of epileptic (EPI) and non-epileptic (NON-EPI) brain tissue and GR-Hsp localization in focal epilepsies. (a) Cresyl violet staining showing dysmorphic region and gross disorganization in cellular pattern in mostly EPI compared with NON-EPI regions. The dysmorphic and balloon cells were present more extensively in EPI brain regions compared with NON-EPI. (b–d) Diaminobenzidine (DAB) immunohistochemical staining of GR, Hsp90, and Hsp70 exhibited positive staining, predominantly in the micro-capillaries and across neurons in the lesioned brain areas. Sporadically, Hsp90-positive staining was also noticed in the astrocytes in these EPI regions, which was negligible in NON-EPI regions. The magnified images are provided as insets.



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