Irradiation of rat brain reduces P-glycoprotein expression and function

J. Bart, W. B. Nagengast, R. P. Coppes, T. D. Wegman, W. T.A. Van Der Graaf, H. J.M. Groen, W. Vaalburg, E. G.E. De Vries*, N. H. Hendrikse

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The blood-brain barrier (BBB) hampers delivery of several drugs including chemotherapeutics to the brain. The drug efflux pump P-glycoprotein (P-gp), expressed on brain capillary endothelial cells, is part of the BBB. P-gp expression on capillary endothelium decreases 5 days after brain irradiation, which may reduce P-gp function and increase brain levels of P-gp substrates. To elucidate whether radiation therapy reduces P-gp expression and function in the brain, right hemispheres of rats were irradiated with single doses of 2-25 Gy followed by 10 mg kg-1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg -1), or with fractionated irradiation (4 x 5 Gy) followed by CsA (10 mg kg-1) 5 days later. Additionally, four groups of three rats received 25 Gy once and were killed 10, 15, 20 or 25 days later. The brains were removed and P-gp detected immunohistochemically. P-gp function was assessed by [11C]carvedilol uptake using quantitative autoradiography. Irradiation increased [11C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11C]carvedilol uptake dose-dependently in both hemispheres, but more (P<0.001) in the irradiated hemisphere. Fractionated irradiation resulted in a lost P-gp expression 10 days after start irradiation, which coincided with increased [11C]carvedilol uptake. P-gp expression decreased between day 15 and 20 after single dose irradiation, and increased again thereafter. Rat brain irradiation results in a temporary decreased P-gp function.

Original languageEnglish
Pages (from-to)322-326
Number of pages5
JournalBritish Journal of Cancer
Volume97
Issue number3
DOIs
Publication statusPublished - 31 Jul 2007

Cite this

Bart, J., Nagengast, W. B., Coppes, R. P., Wegman, T. D., Van Der Graaf, W. T. A., Groen, H. J. M., ... Hendrikse, N. H. (2007). Irradiation of rat brain reduces P-glycoprotein expression and function. British Journal of Cancer, 97(3), 322-326. https://doi.org/10.1038/sj.bjc.6603864