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首页> 外文期刊>Frontiers in Neuropharmacology >The 4-Aminopyridine Model of Acute Seizures in vitro Elucidates Efficacy of New Antiepileptic Drugs
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The 4-Aminopyridine Model of Acute Seizures in vitro Elucidates Efficacy of New Antiepileptic Drugs

机译：急性发作的4-氨基吡啶模型体外阐明了新的抗癫痫药的功效

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Up to date, preclinical screening for new antiepileptic substances is performed by a combination of different in vivo models of acute seizures, for which large numbers of animals are necessary. So far, little attention has been paid to in vitro models, which are also able to detect antiepileptic efficacy and in principle could likewise serve for exploratory preclinical screening. One of the established in vitro models of acute seizures is the 4-aminopyridine (4-AP) model. Previous studies have shown that the 4-AP model is capable to recapitulate the antiepileptic efficacy of standard antiepileptic drugs such as valproate or carbamazepine. Here, we employed a dual methodological approach using electrophysiology and optical imaging to systematically test the antiepileptic efficacy of three new-generation antiepileptic drugs with distinct mechanisms of action (lacosamide, zonisamide, and levetiracetam). We found that frequency of 4-AP induced seizure like events (SLE) was the most sensitive parameter to detect dose-dependent antiepileptic effects in these compounds. Specifically, levetiracetam reduced SLE frequency while lacosamide and zonisamide at higher doses completely blocked SLE incidence. Analysis of the intrinsic optical signal additionally revealed a subiculum-specific reduction of the area involved in the propagation of ictal activity when lacosamide or zonisamide were administered. Taken together, our data adds some evidence that acute seizure models in vitro are in principle capable to detect antiepileptic effects across different mechanisms of action with efficacy similar to acute models in vivo. Further studies with negative controls, e.g. penicillin as a proconvulsant, and other clinically relevant antiepileptic drugs are needed to determine if this acute in vitro model might be useful as exploratory screening tool. In view of the increasing sensitivity towards animal welfare, an affective in vitro model may help to reduce the number of laboratory animals deployed in burdening in vivo experiments and to preselect substances for subsequent testing in time- and cost-laborious models of chronic epilepsy.
机译：迄今为止，新的抗癫痫药物的临床前筛查是通过急性癫痫的不同体内模型的组合进行的，为此需要大量的动物。迄今为止，很少关注体外模型，该模型也能够检测抗癫痫药的功效，并且原则上也可以用于探索性的临床前筛查。建立的急性癫痫发作的体外模型之一是4-氨基吡啶（4-AP）模型。先前的研究表明，4-AP模型能够概括标准抗癫痫药（如丙戊酸盐或卡马西平）的抗癫痫功效。在这里，我们采用电生理学和光学成像的双重方法，系统地测试了三种具有不同作用机理的新一代抗癫痫药（乳糖酰胺，唑尼沙胺和左乙拉西坦）的抗癫痫功效。我们发现4-AP诱发癫痫样事件（SLE）的频率是检测这些化合物中剂量依赖性抗癫痫作用的最敏感参数。具体而言，左乙拉西坦降低了SLE频率，而高剂量的拉考酰胺和唑尼沙胺则完全阻止了SLE的发生。对内在光信号的分析还显示，当给予拉可酰胺或唑尼沙胺治疗时，与眼动活性的传播有关的区域的亚眼下特异性减少。综上所述，我们的数据增加了一些证据，表明体外急性发作模型原则上能够检测跨不同作用机制的抗癫痫作用，其功效类似于体内急性模型。阴性对照的进一步研究，例如需要青霉素作为前惊厥药，以及其他临床相关的抗癫痫药，以确定这种急性体外模型是否可用作探索性筛选工具。鉴于对动物福利的敏感性日益提高，情感的体外模型可能有助于减少用于负担体内实验负担的实验动物的数量，并为在慢性癫痫的费时费力的模型中预先选择用于后续测试的物质。

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