血脑屏障中药物转运体高表达是引起癫痫耐药性的重要原因。我们及前人研究显示姜黄素具有抑制多药耐药性和抗癫痫发作的双重潜能，有可能开发成新型多功能抑制剂，与抗癫痫药物（AED）联合治疗耐药性癫痫。但姜黄素抑制癫痫耐药性、调控血脑屏障中药物转运体的疗效和机理尚不清楚，尚无其调控AED脑内转运的研究。我们发现姜黄素能够调控脑血管中ABC转运体的表达，抑制AED转运。据此，我们假设姜黄素通过调控脑内ABC转运体，增加AED脑内浓度，抑制癫痫耐药性。该课题拟在癫痫大/小鼠、离体脑毛细血管、细胞中研究姜黄素纳米粒子对脑内药物转运体的调控及机理，评估其抑制癫痫耐药性的效果，具体包括：制备姜黄素纳米粒子；在癫痫动物中检测其调控AED脑内浓度、抑制癫痫耐药性的作用；研究姜黄素对血脑屏障中ABC转运体的调控及其分子通路。本研究对解析耐药性癫痫中ABC转运体的调控，开发新型抑制剂，推动姜黄素临床应用具有重要意义。

Drug-resistant is a major problem in epilepsy. The ABC transporter in BBB is one of the factors causing drug-resistant epilepsy. Curcumin can inhibit multi-drug resistant in cancer cells, which has the potential to treat drug resistant epilepsy in clinic. However, the mechanism and effectiveness of curcumin in blocking ABC transporter in blood-brain barrier (BBB) and its effect on drug-resistant epilepsy is unclear. Based on our own work, we hypothesize that: Curcumin can inhibit the upregulation of ABC transporters in BBB of epileptic brain through blocking Glu/NMDAR/COX-2 signaling pathway, block the efflux of AEDs, increase AED brain uptake, and improve the treatment of AEDs for patients with drug resistant epilepsy. The objectives in this application are to identify the influence and mechanism of curcumin on the expression and activity of ABC transporters in BBB, and to evaluate the efficacy of curcumin as an add-on drug to treat patients with drug resistant epilepsy. To accomplish the objectives, we will: I. Develop curcumin nanoparticle formulation; II. Determine the influence of curcumin nanoparticles on the expression and activity of ABC transporters in BBB of rat and mouse epilepsy models, brain capillaries, and hBMEC cells; III. Determine the regulation of key molecules in Glu/NMDAR/COX-2 signaling pathway by curcumin nanoparticles; 4) Develop an add-on therapeutic strategy, which combining curcumin nanoparticles and AEDs, to reduce seizures in mice with drug resistant epilepsy. The proposed research is significant because the expected outcomes will potentially provide a new strategy to improve pharmacotherapy in patients with drug resistant epilepsy and Alzheimer’s disease. And it will also illustrate the mechanism underlying the regulation of ABC transporters by curcumin and epileptogenesis.