Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resi
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ORIGINAL ARTICLE
Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resistant Epilepsy Mohammed Hossain 1 & Sherice Williams 1 & Lisa Ferguson 2 & William Bingaman 2 & Arnab Ghosh 3 & Imad M. Najm 2 & Chaitali Ghosh 1,4 Received: 27 January 2020 / Accepted: 24 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Pharmacoresistance in epilepsy is a major challenge to successful clinical therapy. Glucocorticoid receptor (GR) dysregulation can affect the underlying disease pathogenesis. We recently reported that local drug biotransformation at the blood-brain barrier is upregulated by GR, which controls drug-metabolizing enzymes (e.g., cytochrome P450s, CYPs) and efflux drug transporters (MDR1) in human epileptic brain endothelial cells (EPI-ECs). Here, we establish that this mechanism is influenced upstream by GR and its association with heat shock proteins/co-chaperones (Hsps) during maturation, which differentially affect human epileptic (EPI) tissue and brain endothelial cells. Overexpressed GR, Hsp90, Hsp70, and Hsp40 were found in EPI vs. NON-EPI brain regions. Elevated neurovascular GR expression and co-localization with Hsps was evident in the EPI regions with cortical dysplasia, predominantly in the brain micro-capillaries and neurons. A corresponding increase in ATPase activity (*p < 0.05) was found in the EPI regions. The GR-Hsp90/Hsp70 binding patterns indicated a faster chaperone-promoted maturation of GR, leading to its overactivation in both the tissue and EPI-ECs derived from EPI/focal regions and GR silencing in EPI-ECs slowed such GR-Hsp interactions. Significantly accelerated GR nuclear translocation was determined in EPI-ECs following treatment with GR modulators/ligands dexamethasone, rifampicin, or phenytoin. Our findings reveal that overexpressed GR co-localizes with Hsps in the neurovasculature of EPI brain, increased GR maturation by Hsps accelerates EPI GR machinery, and furthermore this change in EPI and NON-EPI GR-Hsp interaction alters with the age of seizure onset in epileptic patients, together affecting the pathophysiology and drug regulation in the epileptic brain endothelium. Keywords Glucocorticoid receptor . Heat shock proteins . Drug resistance . Blood-brain barrier . Nuclear translocation
Introduction Mohammed Hossain and Sherice Williams contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02043-9) contains supplementary material, which is available to authorized users. * Chaitali Ghosh [email protected] 1
Cerebrovascular Research, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
2
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA
3
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
4
Department of Biomedical Engineering and Molecular Medicine, Cleveland Cli
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