Penetration of Dexamethasone into Brain Glucocorticoid Targets Is Enhanced in mdr1A P-Glycoprotein Knockout Mice*

• DOI: 10.1210/endo.139.4.5917
• Publication Date: 2014-01-08T18:14:22Z
• Authors: O. C. Meijer; E. C. M. de Lange; D. D. Breimer; A. G. de Boer; J. O. Workel; E. R. de Kloet
• Keywords: P-glycoprotein

Abstract Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine effect absence its drug-transporting P-glycoprotein product from blood-brain barrier on distribution and cell nuclear uptake of[ 3H]-dexamethasone in brain.[ (4 μg/kg mouse) was administered sc adrenalectomized mdr1a (−/−) (+/+) mice. One hour later, mice decapitated, radioactivity measured homogenates cerebellum, blood, liver following extraction radioactive steroid. The frontal brain cut sections for autoradiography. In cerebellum mutants, amount relative blood about 5-fold higher than observed controls, whereas ratio vs. not different. Using autoradiography, it found that areas expressing glucocorticoid receptor (GR) high abundance, such as hippocampal fields paraventricular nucleus (PVN), showed 10-fold increase radiolabeled retained steroid increased toward levels pituitary, which contains similar density GRs. [3H]-dexamethasone concentration pituitary affected by disruption. GR messenger RNA expression pattern hippocampus different between wild types rules out altered cause enhanced dexamethasone uptake. conclusion, present study demonstrates is resistant penetration because activity at level barrier. data support concept site action blockade stress-induced ACTH release. Dexamethasone poorly substitutes depletion endogenous therefore, this tissue, may condition resembling adrenalectomy.