Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy
Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy
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DOI：
10.1016/j.nbd.2019.104664
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发表时间：
2020-02-01
影响因子：
6.1
通讯作者：
Loescher, Wolfgang
中科院分区：
文献类型：
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作者：
Schidlitzki, Alina;Bascunana, Pablo;Loescher, Wolfgang
癫痫是一种复杂的网络现象，目前尚无法预防或治愈。我们最近提出了基于网络的方法来预防癫痫发生。为了证明概念，我们结合了两种药物（左维替西坦和托吡酯），其中药物-蛋白质相互作用网络的计算机分析表明对癫痫相关蛋白质的大型功能网络具有协同作用。使用颞叶癫痫的海马内红藻氨酸小鼠模型，在自发性复发性癫痫发作（SRS）发作前的潜伏期期间给予药物组合。当治疗终止后通过视频EEG监测定期记录SRS时，确定SRS的发生率和频率显著降低，表明抗癫痫疗效。单药治疗后未观察到此类疗效。此外，左乙拉西坦和苯巴比妥的组合，药物-蛋白质相互作用网络的计算机分析未表明任何显著的药物-药物相互作用，不能有效地改变癫痫的发展。令人惊讶的是，左乙拉西坦/托吡酯组合的有希望的抗癫痫作用是在没有任何显著的神经保护或抗炎作用的情况下获得的，如多模式脑成像和组织病理学所示。左乙拉西坦/托吡酯联合治疗小鼠同侧海马的高通量RNA测序（RNA-seq）显示，先前与癫痫发生相关的几个基因显著差异表达，为未来的机制研究提供了有趣的切入点。总的来说，我们发现了一种新的联合治疗方法，有望预防癫痫。
Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetir-acetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multi modal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.