Moderate-throughput screening for anti-epileptogenic drugs.

抗癫痫药物的中等通量筛选。

• 批准号: 8212572
• 负责人: Kevin J. Staley
• 金额: $ 20.31万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212572
• 关键词: Address; Algorithms; Anesthetics; Anticonvulsants; Antiepileptic Agents; Antiepileptogenic; Biological Assay; Brain; Brain Injuries; Chronic; Classification; Clinical; Clinical Trials; Collaborations; Collection; Computational algorithm; Custom; Data; Detection; Disease; Drug Exposure; Electroencephalography; Engineering; Epilepsy; Epileptogenesis; Exhibits; FDA approved; Funding; Glass; Human; In Vitro; Institutes; Laboratories; Lead; Libraries; Medicine; Modeling; Monitor; Nerve Degeneration; Nervous system structure; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Preclinical Drug Evaluation; Process; Property; Publishing; Recurrence; Research; Research Personnel; Screening procedure; Seizures; Slice; Staging; Stroke; System; Techniques; Technology; Testing; United States National Institutes of Health; base; drug candidate; drug discovery; high throughput screening; in vitro Model; in vivo; in vivo Model; kainate; nervous system disorder; prevent; programs; public health relevance; research clinical testing

DESCRIPTION (provided by applicant): It has been extremely difficult to screen for drugs that prevent epilepsy after brain injury, because spontaneous recurrent seizures begin gradually and the interval between seizures varies widely, so that long-term, intensive seizure monitoring is required to determine whether a drug prevents epilepsy. A rigorous yet rapid screen would enable us to test many promising compounds for anti-epileptogenic properties, and would provide epilepsy researchers with a much-needed assay to test new compounds developed within their laboratories. We have developed a new set of technologies to enable large-scale screening for antiepileptic drugs. In collaboration with the Harvard Center for Engineering in Medicine, we have developed an in vitro model of epileptogenesis comprised of glass chips that can be used to culture, record from, and administer drugs to arrays of 32 organotypic brain slices per chip. We have recently shown that these brain slice cultures undergo a rapid, predictable process of epileptogenesis, and that the organotypic brain slices respond to anticonvulsant drugs just as human patients do. We have recently published computer algorithms for continuously recording and quantifying electrographic spikes and seizures, and in collaboration with Ed Dudek, an investigator in the National Institute of Neurological Diseases and Stroke (NINDS) Anticonvulsant Screening Program, we have validated these algorithms in two in vivo models of epileptogenesis as well as in the in vitro model. We will use our newly-created technologies to execute large-scale, parallel screening of drug libraries for agents that prevent, reduce, or reverse epileptogenesis. One such library is the NINDS Custom Compounds library; we will focus on the 561 compounds that have already been approved by the FDA. We propose to subject these compounds to a rapid, rigorous two stage screen for anti-epileptogenic properties. In the first stage, we will screen compounds using parallel cultured brain slice assays. Compounds that prevent, reduce, or reverse epileptogenesis will then progress to the second stage, in which the most promising compounds will be subjected to a more rigorous albeit much slower second assay, the kainate model of epileptogenesis. In both stages, electrographic seizure activity will be assayed quantitatively using continuously recorded and analyzed EEG data. This research will lead to a U01. The results of the R21-funded screening project may produce compounds that are sufficiently active to begin clinical testing. Alternatively, the R21 will provide lead compounds that will enable us to apply for the NINDS Blueprint Grand Challenge for New Drugs for Diseases and Disorders of the Nervous System, so that we can screen larger compound libraries and optimize compounds in collaboration with the medicinal chemists at The Laboratory for Drug Discovery in Neurodegeneration (LDDN) in the Harvard NeuroDiscovery Center. PUBLIC HEALTH RELEVANCE: It has not been possible to screen for drugs that prevent epilepsy after brain injury, because seizures begin to occur very gradually, and the interval between seizures varies widely, so that long-term, intensive seizure monitoring is required to determine whether a drug prevents epilepsy. We have developed a set of technologies that makes possible the application of large-scale screening strategies to this problem. Cultured brain slices that become spontaneously epileptic will be deployed in a highly parallel screening program as a first stage in screening. In vivo testing will be used to confirm the effects of the most promising agents found in the first stage of screening.

描述（由申请人提供）：由于自发的复发性癫痫发作开始逐渐开始，并且癫痫发作之间的间隔差异很大，因此很难筛查预防脑损伤后癫痫的药物，因此需要长期，密集的癫痫发作监测以确定药物是否患有癫痫病。严格而快速的屏幕将使我们能够测试许多有前途的抗癫痫发作特性的化合物，并将为癫痫研究人员提供急需的测定法，以测试其实验室中开发的新化合物。我们已经开发了一套新的技术，以实现抗癫痫药的大规模筛查。通过与哈佛医学工程中心合作，我们开发了一种体外的癫痫发生模型，该模型由玻璃芯片组成，可用于培养，记录和施用药物，每芯片32个器官脑切片的阵列。我们最近表明，这些大脑切片培养物经历了快速，可预测的癫痫生成过程，并且像人类患者一样，器官型脑切片对抗惊厥药的反应。我们最近发表了用于连续记录和量化电视峰值和癫痫发作的计算机算法，并与国家神经疾病和中风研究所（NINDS）抗惊厥筛选程序的研究人员埃德·杜德克（Ed Dudek）合作，我们已经验证了两个Invivo模型的epiLeptoseisospoteans and Vetro and Insodro，又是Insover and Inso n of and Inso，我们已经验证了这些算法。我们将使用新创建的技术对预防，减少或反向癫痫发生的药物进行大规模的，平行筛选。一个这样的库就是Ninds自定义化合物库；我们将重点关注FDA已经批准的561种化合物。我们建议对这些化合物进行抗癫痫发作特性的快速，严格的两阶段筛选。在第一阶段，我们将使用平行培养的脑切片测定法筛选化合物。预防，减少或反向癫痫发生的化合物将发展到第二阶段，其中最有希望的化合物将受到更严格的第二种测定，即癫痫生成的海藻酸盐模型。在这两个阶段中，将使用连续记录和分析的脑电图数据对电视癫痫发作活性进行定量测定。这项研究将导致U01。 R21资助的筛选项目的结果可能会产生足够活跃以开始临床测试的化合物。另外，R21将提供铅化合物，使我们能够针对神经系统的疾病和疾病的新药申请NINDS蓝图巨大挑战，以便我们可以筛选更大的化合物库，并在神经变性（Ldddnneurods）中与药物发现在实验室中与药物发现的药物研究中的药物合作中的化合物优化。 公共卫生相关性：由于癫痫发作开始非常逐渐发生，因此不可能筛查预防脑损伤后癫痫的药物，并且癫痫发作之间的间隔变化很大，因此需要长期，密集的癫痫发作监测来确定药物是否预防癫痫病。我们已经开发了一系列技术，使大规模筛选策略成为可能。自发癫痫的培养大脑切片将在高度平行的筛选程序中部署，作为筛查的第一阶段。体内测试将用于确认在筛查第一阶段发现的最有前途的药物的影响。

项目成果

Interictal spikes, seizures and ictal cell death are not necessary for post-traumatic epileptogenesis in vitro.

• DOI: 10.1016/j.nbd.2011.11.001
• 发表时间: 2012-02
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Berdichevsky, Yevgeny;Dzhala, Volodymyr;Mail, Michelle;Staley, Kevin J.
• 通讯作者: Staley, Kevin J.