Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice

Endocrinology
O C MeijerE R De Kloet

Abstract

Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-transporting P-glycoprotein product from the blood-brain barrier on the distribution and cell nuclear uptake of [3H]-dexamethasone in the brain. [3H]-dexamethasone (4 microg/kg mouse) was administered s.c. to adrenalectomized mdr1a (-/-) and mdr1a (+/+) mice. One hour later, the mice were decapitated, and the radioactivity was measured in homogenates of cerebellum, blood, and liver following extraction of the radioactive steroid. The frontal brain was cut in sections for autoradiography. In the cerebellum of the mdr1a mutants, the amount of [3H]-dexamethasone relative to blood was about 5-fold higher than observed in the controls, whereas the ratio in blood vs. liver was not different. Using autoradiography, it was found that brain areas expressing the glucocorticoid receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in cell nuclear uptake of radiolabeled steroid. The amount of retained steroid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [3H]-dexamethasone concen...Continue Reading

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Citations

Sep 14, 2011·Proceedings of the National Academy of Sciences of the United States of America·Conor Liston, Wen-Biao Gan
Oct 1, 2008·BMC Biotechnology·Suzanne ZeitouniDarwin J Prockop
Dec 10, 2009·PloS One·Gijs KooijHelga E de Vries
Nov 20, 2013·Frontiers in Neuroendocrinology·Robert J Handa, Michael J Weiser
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