Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy
Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy
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DOI：
10.1007/s11064-017-2227-7
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发表时间：
2017-07-01
影响因子：
4.4
通讯作者：
Wilcox, Karen S.
中科院分区：
文献类型：
--
作者：
Barker-Haliski, Melissa L.;Johnson, Kristina;Wilcox, Karen S.
成功识别用于治疗癫痫的有前途的研究疗法可以归功于80多年来使用的众多癫痫发作和癫痫动物模型。在这段时间里，小鼠和大鼠的最大电休克试验，小鼠和大鼠的皮下戊四唑试验，以及最近的小鼠6 Hz试验，已被用作神经系统完整的啮齿动物的电或化学诱发癫痫发作的主要模型。此外，啮齿动物点燃模型，其中慢性网络过度兴奋已经发展，已被用于确定新的代理。很明显，这种传统的筛查方法大大增加了可用于管理癫痫相关症状性发作的上市药物的数量。尽管目前市场上有许多抗癫痫药物（ASD），但事实仍然是近30%的患者对这些现有药物具有耐药性。为了解决这一未满足的医疗需求，美国国家神经疾病和卒中研究所（NINDS）癫痫治疗筛查项目（ETSP）于2015年修订了其对治疗癫痫的研究药物的早期评估方法，以重点关注临床前方法来模拟药物耐药性癫痫发作。本报告强调了在体内和体外的研究结果与初步药理学验证这种测试方法使用了一些不同的机制，市售的抗癫痫药物，以及几个探针化合物是潜在的机制感兴趣的癫痫的临床管理。
The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.