SIGNALING TO P-GLYCOPROTEIN-A NEW THERAPEUTIC TARGET TO TREAT DRUG-RESISTANT EPILEPSY?
SIGNALING TO P-GLYCOPROTEIN-A NEW THERAPEUTIC TARGET TO TREAT DRUG-RESISTANT EPILEPSY?
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DOI：
10.1358/dnp.2009.22.7.1401354
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发表时间：
2009-09-01
影响因子：
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通讯作者：
Bauer, Bjoern
中科院分区：
文献类型：
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作者：
Hartz, Anika M. S.;Notenboom, Sylvia;Bauer, Bjoern
全世界有超过 6000 万人患有癫痫症。虽然大多数患者可以接受抗癫痫药物治疗，但高达 40% 的患者对药物治疗反应不佳。这种耐药性尚未被充分理解，并且是一个主要的临床问题。在这篇简短的综述中，我们提供了抗癫痫药物耐药性的一个潜在原因的背景信息，即血脑屏障处药物流出转运蛋白 P-糖蛋白的上调。我们总结了最近的研究结果，将抗癫痫药物耐药性与 P-糖蛋白上调联系起来，并显示了癫痫发作和该转运蛋白上调之间的机制联系。我们提供了结果概述，证明癫痫发作期间释放的谷氨酸通过 N-甲基-D-天冬氨酸 (NMDA) 受体和环氧合酶-2 (COX-2) 发出信号以增加 P-糖蛋白。在此背景下，我们讨论 NMDA 受体和 COX-2 作为潜在的治疗靶点，并提供有关涉及血脑屏障外排转运蛋白的耐药性癫痫的当前临床试验的信息。最后，我们对未来的研究提出了展望，这有助于改善耐药性癫痫的治疗。
Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background information on one potential cause of antiepileptic drug resistance, namely, upregulation of the drug efflux transporter P-glycoprotein at the blood-brain barrier. We summarize recent findings that connect antiepileptic drug resistance with P-glycoprotein upregutation and show a mechanistic link between seizures and upregutation of this transporter. We provide an overview of results demonstrating that glutamate released during seizures signals through N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) to increase P-glycoprotein. In this context we discuss the NMDA receptor and COX-2 as potential therapeutic targets and provide information on current clinical trials on drug-resistant epilepsy involving blood-brain barrier efflux transporters. Finally, we provide a perspective on future research that could help improve the treatment of drug-resistant epilepsy.