CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; UDI-IPG, Research Unit for Inland Development, Polytechnic Institute of Guarda, 6300-749 Guarda, Portugal.
Food Res Int. 2018 Jan;103:110-120. doi: 10.1016/j.foodres.2017.10.010. Epub 2017 Oct 12.
The pharmacoresistance to antiepileptic drugs (AEDs) remains a major unsolved therapeutic need. The overexpression of multidrug transporters, as the P-glycoprotein (P-gp), at the level of the blood-brain barrier of epileptic patients has been suggested as a key mechanism underlying the refractory epilepsy. Thus, efforts have been made to search for therapeutically useful P-gp inhibitors. Herein, the strategy of flavonoid/AED combined therapy was exploited as a possible approach to overcome the P-gp-mediated pharmacoresistance. For this purpose, several in vitro studies were performed using Madin-Darby canine kidney II (MDCK II) cells and those transfected with the human multidrug resistance-1 (MDR1) gene, overexpressing the P-gp (MDCK-MDR1). Overall, the results showed that baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin, at 200μM, produced a marked increase on the intracellular accumulation of rhodamine 123 in MDCK-MDR1 cells, potentially through inhibiting the P-gp activity. In addition, with the exception of lamotrigine, all other AEDs tested (phenytoin, carbamazepine and oxcarbazepine) and their active metabolites (carbamazepine-10,11-epoxide and licarbazepine) demonstrated to be P-gp substrates. Furthermore, the most promising flavonoids as P-gp inhibitors promoted a significant increase on the intracellular accumulation of the AEDs (excluding lamotrigine) and their active metabolites in MDCK-MDR1 cells, evidencing to be important drug candidates to reverse the AED-resistance. Thus, the co-administration of AEDs with baicalein, (-)-epigallocatechin gallate, kaempferol, quercetin and silymarin should continue to be explored as adjuvant therapy for refractory epilepsy. List of chemical compounds studied in this article: Baicalein (PubChem CID: 5,281,605); Carbamazepine (PubChem CID: 2554); Carbamazepine 10,11-epoxide (PubChem CID: 2555); (-)-Epigallocatechin gallate (PubChem CID: 65064); Kaempferol (PubChem CID: 5280863); Lamotrigine (PubChem CID: 3878); Licarbazepine (PubChem CID: 114709); Oxcarbazepine (PubChem CID: 34312); Phenytoin (PubChem CID: 1775); Silymarin (PubChem CID: 7073228); Quercetin (PubChem CID: 5280343); Verapamil (PubChem CID: 2520).
抗癫痫药物（AED）的耐药性仍然是一个未解决的主要治疗需求。在癫痫患者的血脑屏障水平，多药转运蛋白（如 P-糖蛋白（P-gp））的过度表达被认为是难治性癫痫的关键机制之一。因此，人们一直在努力寻找治疗上有用的 P-gp 抑制剂。在此，本文利用黄酮类/AED 联合治疗策略作为克服 P-gp 介导的耐药性的可能方法。为此，使用 Madin-Darby 犬肾 II（MDCK II）细胞和转染人多药耐药基因 1（MDR1）的细胞（过表达 P-gp（MDCK-MDR1））进行了几项体外研究。总的来说，结果表明，黄芩素、（-）-表没食子儿茶素没食子酸酯、山奈酚、槲皮素和水飞蓟素在 200μM 时，可显著增加 MDCK-MDR1 细胞中罗丹明 123 的细胞内积累，可能是通过抑制 P-gp 活性。此外，除拉莫三嗪外，测试的所有其他 AED（苯妥英、卡马西平和奥卡西平）及其活性代谢物（卡马西平-10,11-环氧和利卡西平）均被证明是 P-gp 底物。此外，作为 P-gp 抑制剂最有前途的黄酮类化合物可显著增加 MDCK-MDR1 细胞中 AED（不包括拉莫三嗪）及其活性代谢物的细胞内积累，表明它们是逆转 AED 耐药性的重要候选药物。因此，应继续探索将 AED 与黄芩素、（-）-表没食子儿茶素没食子酸酯、山奈酚、槲皮素和水飞蓟素联合给药作为难治性癫痫的辅助治疗。本文研究的化合物列表：黄芩素（PubChem CID：5,281,605）；卡马西平（PubChem CID：2554）；卡马西平 10,11-环氧（PubChem CID：2555）；（-）-表没食子儿茶素没食子酸酯（PubChem CID：65064）；山奈酚（PubChem CID：5280863）；拉莫三嗪（PubChem CID：3878）；利卡西平（PubChem CID：114709）；奥卡西平（PubChem CID：34312）；苯妥英（PubChem CID：1775）；水飞蓟素（PubChem CID：7073228）；槲皮素（PubChem CID：5280343）；维拉帕米（PubChem CID：2520）。
