Decreased expression of multidrug efflux transporters in the brains of GSK-3β transgenic mice
Journal Publication ResearchOnline@JCUAbstract
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-3β) transgene, driven by the Thy-1 promoter so limiting its localization predominantly to neurons and some glial cells. As expected, decreases in β-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-3β activity that alter signaling via β-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.
Journal
Brain Research
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Volume
1276
ISBN/ISSN
1872-6240
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Pages Count
10
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Publisher
Elsevier
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EISSN
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DOI
10.1016/j.brainres.2009.04.031