Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.

中文翻译：

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血脑屏障处 P-糖蛋白的调节：改善中枢神经系统药物治疗的机会。

中枢神经系统 (CNS) 疾病（例如，神经退行性疾病、癫痫、脑癌和神经艾滋病）的药物治疗受到血脑屏障的限制。P-糖蛋白是一种 ATP 驱动的药物外排转运蛋白，是该屏障的关键元素。高表达水平、腔膜定位、多特异性和高转运能力使 P-糖蛋白成为血脑屏障的选择性看门人，因此是药物进入大脑的主要障碍。因此，P-糖蛋白限制了大量处方药进入中枢神经系统，导致中枢神经系统候选药物的成功率低，并且可能导致中枢神经系统药物治疗的患者间差异。因此，调节 P-糖蛋白可以改善药物输送到大脑中。在这里，我们回顾了目前对调节血脑屏障 P-糖蛋白活性/表达的信号机制的理解，重点是我们实验室最近的研究。使用来自大鼠和小鼠的完整脑毛细血管，我们已经确定了调节这种转运蛋白的多种细胞外和细胞内信号；已经绘制了几个信号通路。三种途径是由大脑先天免疫反应的元素触发的，一种是谷氨酸，一种是异生物质-核受体（孕烷 X 受体）相互作用，另一种是β-淀粉样蛋白水平升高。信号传导很复杂，有几个通路共享共同的信号传导元件 [肿瘤坏死因子 (TNF) 受体 1、内皮素 (ET) B 受体、蛋白激酶 C 和一氧化氮合酶)，表明存在调节网络。几种途径包括自分泌/旁分泌元件，涉及促炎细胞因子 TNF-α 和多肽激素 ET-1 的释放。最后，信号传导的几个步骤是潜在的治疗靶点，可用于调节临床中的 P-糖蛋白活性。