English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Summary   Objective  Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes ( CYP s) to the drug‐resistant phenotype in human epilepsy. However, the upstream molecular regulators of  CYP  in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic ( PXR ) and glucocorticoid ( GR ) nuclear receptors in endothelial cells established from post‐epilepsy surgery brain samples.    Methods   PXR / GR  localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug‐resistant seizures. We used primary cultures of endothelial cells obtained from epileptic brain tissues ( EPI ‐ EC s; n = 8), commercially available human brain microvascular endothelial cells ( HBMEC s; n = 8), and human hepatocytes (n = 3).  PXR / GR  messenger RNA ( mRNA ) levels in brain  EC s was initially determined by complementary DNA (cDNA) microarrays. The expression of  PXR / GR  proteins was quantified by Western blot.  PXR  and  GR  silencing was performed in  EPI ‐ EC s (n = 4), and the impact on downstream  CYP  expression was determined.    Results   PXR / GR  expression was detected by immunofluorescence in ECs and neurons in the human temporal lobe samples analyzed. Elevated  mRNA  and protein levels of  PXR  and  GR  were found in  EPI ‐ EC s versus control  HBMEC s. Hepatocytes, used as a positive control, displayed the highest levels of  PXR / GR  expression. We confirmed expression of  PXR / GR  in cytoplasmic‐nuclear subcellular fractions, with a significant increase of  PXR / GR  in  EPI ‐ EC s versus controls.  CYP 3A4,  CYP 2C9, and  CYP 2E1 were overexpressed in  EPI ‐ EC s versus control, whereas  CYP 2D6 and  CYP 2C19 were downregulated or absent in  EPI ‐ EC s.  GR  silencing in  EPI ‐ EC s led to decreased  CYP 3A4,  CYP 2C9, and  PXR  expression.  PXR  silencing in  EPI ‐ EC s resulted in the specific downregulation of  CYP 3A4 expression.    Significance  Our results indicate increased  PXR  and  GR  in primary ECs derived from human epileptic brains.  PXR  or  GR  may be responsible for a local drug brain metabolism sustained by abnormal  CYP  regulation.

Overexpression of pregnane X and glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells