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（申请人提供）：筛选预防脑损伤后癫痫的药物极其困难，因为自发性复发性癫痫发作是逐渐开始的，且癫痫发作间隔时间差异很大，因此需要长期、严密的癫痫发作监测来确定药物是否可以预防癫痫。严格而快速的筛选将使我们能够测试许多有前景的化合物的抗癫痫特性，并为癫痫研究人员提供急需的检测方法来测试其实验室开发的新化合物。我们开发了一套新技术，可以大规模筛选抗癫痫药物。我们与哈佛医学工程中心合作，开发了一种癫痫发生的体外模型，该模型由玻璃芯片组成，可用于对每个芯片 32 个器官型脑切片的阵列进行培养、记录和给药。我们最近表明，这些脑切片培养物经历了一个快速、可预测的癫痫发生过程，并且器官型脑切片对抗惊厥药物的反应就像人类患者一样。我们最近发布了用于连续记录和量化电图尖峰和癫痫发作的计算机算法，并与美国国家神经疾病和中风研究所 (NINDS) 抗惊厥筛查项目的研究员 Ed Dudek 合作，在两种体内验证了这些算法癫痫发生模型以及体外模型。我们将利用我们新创建的技术对药物库进行大规模、平行筛选，寻找预防、减少或逆转癫痫发生的药物。 NINDS 定制化合物库就是此类库之一；我们将重点关注已获得 FDA 批准的 561 种化合物。我们建议对这些化合物进行快速、严格的两阶段筛选，以确定其抗癫痫特性。在第一阶段，我们将使用平行培养脑切片测定来筛选化合物。然后，预防、减少或逆转癫痫发生的化合物将进入第二阶段，其中最有希望的化合物将接受更严格但慢得多的第二次测定，即癫痫发生的红藻氨酸模型。在这两个阶段，将使用连续记录和分析的脑电图数据对电图癫痫发作活动进行定量分析。这项研究将导致 U01。 R21 资助的筛选项目的结果可能会产生具有足够活性以开始临床测试的化合物。或者，R21 将提供先导化合物，使我们能够申请 NINDS 神经系统疾病和紊乱新药蓝图大挑战，以便我们可以与药物化学家合作筛选更大的化合物库并优化化合物。哈佛神经发现中心的神经退行性疾病药物发现实验室 (LDDN)。 公共卫生相关性：目前还不可能筛选出脑损伤后预防癫痫的药物，因为癫痫发作是逐渐发生的，并且癫痫发作之间的间隔差异很大，因此需要长期、严密的癫痫发作监测来确定是否存在癫痫发作。有一种药物可以预防癫痫。我们开发了一套技术，使大规模筛选策略应用到这个问题成为可能。自发性癫痫的培养脑切片将被部署在高度并行的筛查计划中，作为筛查的第一阶段。体内测试将用于确认在筛选的第一阶段发现的最有希望的药物的效果。

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.