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Experimental Genetics Group
Brain Res. 2009 Jun 18;1276:1-10. Lim JC1, Mickute Z1, Zaman M1, Hopkins S1, Wijesuriya H1, Steckler T2, Moechars D2, Van Leuven F3, Sarnyai Z1, Hladky SB1, Barrand MA1*. 1Department of Pharmacology, Unviersity of Cambridge, Cambridge, UK. 2Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium. 3Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. *Corresponding author. Multidrug efflux transporters protect cells in the brain from potentially harmful substances but also from therapeutically useful drugs. Thus any condition that causes changes in their expression is of some importance with regard to drug access. In this study, changes in efflux transporter expression are investigated in mice containing a mutant constitutively active glycogen synthase kinase-3 (GSK-3beta) transgene, driven by the Thy-1 promoter so limiting its localization predominantly to neurons and some glial cells. As expected, decreases in beta-catenin were evident via Western blot analyses of cortical homogenates prepared from brains of these transgenic mice. As assessed by real time qRT-PCR, decreased transcript levels of the mdr1b isoform of P-glycoprotein, Mrp1 and Mrp4, (transporters associated with neurons and/or glial cells) were observed in the cortex but not the subventricular zone or hippocampus of the transgenic compared to wild type mouse brains. By contrast, no such decreases were evident with the mdr1a isoform of P-glycoprotein and Bcrp, transporters predominantly found in brain endothelium. Such transporter expression changes could not be accounted for by alterations in blood vessel density or neuronal to glial cell ratios as analyzed both from immunocytochemical staining and from RT-PCR. These observations support previous in vitro data showing that manipulations to GSK-3beta activity that alter signaling via beta-catenin can influence the expression of efflux transporters. Implications from this are that drug distribution into cells within the brain of these transgenic mice could be enhanced, hence warranting further investigation.  FULL TEXT |
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