Löscher Wolfgang
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, 30559, Hanover, Germany.
Center for Systems Neuroscience, Hanover, Germany.
Neurochem Res. 2017 Jul;42(7):1873-1888. doi: 10.1007/s11064-017-2222-z. Epub 2017 Mar 13.
The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.
确定用于治疗癫痫的潜在治疗药物需要使用癫痫发作模型。除了一些早期治疗方法，包括溴化物和苯巴比妥外，所有临床使用药物的抗癫痫活性在很大程度上是通过啮齿动物的急性癫痫发作模型来定义的，这些模型使用最大电休克和皮下注射戊四氮癫痫发作试验以及电点燃大鼠。不幸的是，迄今为止的临床证据表明，尽管这些模型很有用，但它们都不太可能识别出能有效治疗耐药性癫痫患者的治疗方法。在过去30年中，已经开发出了许多表现出不同程度耐药性的动物模型，如苯妥英或拉莫三嗪耐药的点燃大鼠、部分性癫痫发作的6赫兹小鼠模型、小鼠海马内注射海藻酸模型，或通过化学或电刺激诱发癫痫持续状态后出现自发性反复癫痫发作的大鼠。因此，这些模型可用于研究耐药机制，并可能为识别真正新型的抗癫痫药物（ASD）提供独特机会，但迄今为止，这一希望缺乏临床证据。尽管耐药性癫痫的动物模型现在已被纳入ASD发现方法中，如癫痫治疗筛选计划（ETSP），但需要注意的是，没有一个单一模型已被验证可用于识别针对尚未耐药癫痫的潜在化合物，而应使用一系列此类模型，从而提高发现新型、高效ASD的敏感性。本综述描述了以往和当前在寻找新ASD时所采用的方法，并对纳入新出现的治疗耐药性动物模型的未来方向提供了一些见解。
