Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
J Cereb Blood Flow Metab. 2011 Jun;31(6):1371-5. doi: 10.1038/jcbfm.2011.44. Epub 2011 Apr 13.
Upregulation of blood-brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-β1 (PKC-β1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-β1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-β1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries and reversed the effect of dioxin on brain uptake of verapamil in dioxin-dosed rats. Thus, targeting BBB PKC-β1 may be an effective strategy to improve drug delivery to the brain, even in drug-resistant individuals.
血脑屏障（BBB）P-糖蛋白表达上调导致中枢神经系统（CNS）药物耐药性。然而，BBB 蛋白激酶 C-β1（PKC-β1）的激活会迅速降低基础 P-糖蛋白转运活性。我们测试了 PKC-β1 的激活是否会逆转二恶英通过芳香烃受体引起的 CNS 药物耐药性。选择性 PKC-β1 激动剂可消除二恶英在分离的大鼠脑毛细血管中诱导的 P-糖蛋白活性增加，并逆转二恶英对二恶英给药大鼠维拉帕米脑摄取的影响。因此，靶向 BBB PKC-β1 可能是一种提高药物向大脑递送的有效策略，即使在耐药个体中也是如此。
