Despite the approval of a considerable number of last generation antiepileptic drugs (AEDs) (only in the last decade, six drugs have gained Food and Drug Administration approval), the global figures of seizure control have seemingly not improved, and available AED can still be regarded as symptomatic treatments. Fresh thinking in AEDs drug discovery, including the development of drugs with novel mechanisms of action, is required to achieve truly innovative antiepileptic medications. The transporter hypothesis proposes that inadequate penetration of AEDs across the blood-brain barrier, caused by increased expression of efflux transporters such as P-glycoprotein (P-gp), contributes to drug-resistant epilepsy. Neuroinflammation due to high levels of glutamate has been identified as one of the causes of P-gp upregulation, and several studies in animal models of epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of refractory epilepsy. We have applied ligand-based in silico screening to select compounds that exert dual anticonvulsant and antiinflammatory effects. Five of the hits were tested in animal models of seizure, with protective effects. Later, two of them (sebacic acid (SA) and gamma-decanolactone) were submitted to the recently described MP23 model of drug-resistant seizures. All in all, SA displayed the best profile, showing activity in the maximal electroshock seizure (MES) and pentylenetetrazol (PTZ) seizure models, and reversing resistance to phenytoin (PHT) and decreasing the P-gp upregulation in the MP23 model. Furthermore, pretreatment with SA in the pilocarpine status epilepticus (SE) model resulted in decreased histamine release in comparison with nontreated animals. This is the first report of the use of the MP23 model to screen for novel anticonvulsant compounds that may avoid the development of P-gp-related drug resistance.

中文翻译：

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新的抗惊厥候选药物可防止小鼠抗药性癫痫模型中 P-糖蛋白 (P-gp) 的过度表达

尽管上一代抗癫痫药（AEDs）获得了相当数量的批准（仅在最近十年，就有六种药物获得了食品药品监督管理局的批准），但全球缉获量控制数字似乎没有改善，可用的AED仍然可以视为对症治疗。AEDs 药物发现的新思维，包括开发具有新作用机制的药物，是实现真正创新的抗癫痫药物所必需的。转运蛋白假说认为，由于外排转运蛋白如 P-糖蛋白 (P-gp) 的表达增加，AED 对血脑屏障的渗透不足会导致耐药性癫痫。由高水平谷氨酸引起的神经炎症已被确定为 P-gp 上调的原因之一，癫痫动物模型中的几项研究表明，抗炎药可能会阻止 P-gp 过度表达，从而避免难治性癫痫的发展。我们已应用基于配体的计算机筛选来选择具有双重抗惊厥和抗炎作用的化合物。其中五个命中在癫痫发作的动物模型中进行了测试，具有保护作用。后来，其中的两种（癸二酸 (SA) 和 γ-癸内酯）被提交给最近描述的抗药性癫痫发作的 MP23 模型。总而言之，SA 表现出最好的特征，在最大电击癫痫 (MES) 和戊四唑 (PTZ) 癫痫模型中显示出活性，并在 MP23 模型中逆转苯妥英 (PHT) 抗性并降低 P-gp 上调。此外，与未处理的动物相比，在毛果芸香碱癫痫持续状态 (SE) 模型中用 SA 预处理导致组胺释放减少。这是使用 MP23 模型筛选可能避免 P-gp 相关耐药性发展的新型抗惊厥化合物的第一份报告。