Validation of High-Throughput Screening of Candidate Antiepileptogenic Drugs

候选抗癫痫药物高通量筛选的验证

基本信息

批准号：
7869112
负责人：
ANDREY M MAZARATI
金额：
$ 8.58万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7869112
关键词：
Adolescent Adult Affect Age Animal Model Animals Antiepileptic Agents Antiepileptogenic Behavioral Biological Assay Bumetanide Chronic Databases Development Diazepam Disease Drug Evaluation Electric Stimulation Epilepsy Epileptogenesis Ethosuximide Evaluation Evolution Experimental Models Failure Frequencies Future Goals Hippocampus (Brain)Hour Human Individual Injection of therapeutic agent Kindling (Neurology)Levetiracetam Maps Modeling Modification Monitor Nature Neonatal Nerve Degeneration Neurons Pattern Pharmaceutical Preparations Phenytoin Plastics Prevention Preventive Procedures Process Property Recurrence Research Scanning Screening procedure Seizures Severities Staging Status Epilepticus Therapeutic Agents Time Validation Valproate Sodium Vigabatrin base clinically relevant cost design drug discovery felbamate gabapentin ganaxolone high throughput screening in vivo lamotrigine pre-clinical preclinical study prevent prospective response therapy development topiramate

项目摘要

DESCRIPTION (provided by applicant): Understanding mechanisms that underlie the evolution of chronic epilepsy (i.e. epileptogenesis) is instrumental for developing effective preventive therapies of the epileptic process. In turn, the development and validation of clinically relevant animal models are needed that could be used for both basic and preclinical studies. The majority of currently available models of epileptogenesis employ a precipitating insult (e.g. status epilepticus, SE), which leads to progressive neurodegenerative and neuronal plastic changes, and culminates in the occurrence of spontaneous recurrent seizures. While being indispensable for basic epilepsy research, the inherent features of these models (e.g. slow progression; high inter-animal and temporal variability of seizure frequency and severity; unpredictability of individual seizure occurrence) represent significant challenges for preclinical antiepileptic drug (AED) evaluation due to time, labor and costs involved. The objective of the proposed project is to validate a high-throughput screening assay for rapid identification and evaluation of antiepileptogenic and/or disease-modifying drugs. We propose that the rapid kindling model of epileptogenesis can be used for AED drug discovery. The validation will consist of analysis of the effects of fifteen compounds with established pharmacological profiles (bumetanide, diazepam, ethosuximide felbamate, gabapentin, ganaxolone, lamotrigine, levetiracetam, MK-801; phenytoin, retigabine, topiramate, valproate sodium, vigabatrin, zonisamide) on rapid kindling epileptogenesis in experimental animals of five different ages (neonatal; post-neonatal; pre-adolescent; adolescent; adult). Rapid kindling will be induced by 60 electrical stimulations delivered to the hippocampus every 5 minutes at a suprathreshold current (total procedure duration is 5 hours). The animals will receive a single injection of an AED prior to kindling; the progression and the pattern of electrographic and behavioral seizures will be monitored and analyzed. AEDs are chosen so that, based on the mechanisms of their action and known mechanisms of epileptogenesis, they are expected to modify seizure progression in different ways, including complete prevention of seizures (antiepileptogenic effect), mitigation of epileptic process (disease modification), and failure to affect seizures at all. As a result of the study, we will generate an expanded pharmacological profile of the rapid kindling model of epileptogenesis. The compiled database can then be used for mapping of emerging antiepileptogenic drugs against known AEDs in terms of their efficiency. The progressive nature of epilepsy (epileptogenesis) dictates the necessity for developing therapies that can block the epileptic process during its early stages. In turn, the introduction and validation of experimental models that would (a) closely resemble human condition, and (b) allow large scale screening of prospective antiepileptogenic drugs are required. The current project is designed to introduce and validate an animal model of epileptogenesis that would allow for the quick and effective screening of emerging antiepileptogenic drugs on a large scale.

描述（由申请人提供）：理解慢性癫痫演化（即癫痫发生）的基础的机制对开发癫痫过程的有效预防疗法具有重要作用。反过来，需要用于基础研究和临床前研究的临床相关动物模型的开发和验证。当前可用的癫痫生成模型中，大多数都采用沉淀的损伤（例如状态癫痫，SE），这会导致进行性神经退行性和神经元的塑性变化，并在自发性癫痫发作的发生中达到顶点。尽管对于基本癫痫研究是必不可少的，但这些模型的固有特征（例如，慢速进展；癫痫发作频率和严重程度的高动物间和时间变异性；个人癫痫发作的不可预测性）代表了由于时间，劳动和成本所带来的时间，劳动药物（AED）评估的重大挑战。拟议项目的目的是验证高通量筛查测定法，以快速鉴定和评估抗癫痫发作和/或疾病改良药物。我们建议将癫痫发生的快速点燃模型用于AED药物发现。 The validation will consist of analysis of the effects of fifteen compounds with established pharmacological profiles (bumetanide, diazepam, ethosuximide felbamate, gabapentin, ganaxolone, lamotrigine, levetiracetam, MK-801; phenytoin, retigabine, topiramate, valproate sodium, vigabatrin, zonisamide) on在五个不同年龄的实验动物（新生儿；否决后；青春期前；青少年；成人）中快速生进癫痫发生。快速点燃将由每5分钟在上库电流下每5分钟传递到海马的60个电刺激（总过程持续时间为5小时）。动物将在点燃之前单次注射AED；将监测和分析电图和行为癫痫发作的进展和模式。选择AED，以便根据其作用机制和已知的癫痫发生机制，预计它们将以不同的方式修饰癫痫发作的进展，包括完全预防癫痫发作（抗癫痫发作），缓解癫痫病过程（疾病修饰）以及失败在所有方面影响癫痫发作。这项研究的结果是，我们将产生癫痫生成快速点燃模型的药理学特征。然后，根据其效率，可以将编译的数据库用于针对已知AED的新兴抗癫痫药物。癫痫的渐进性（癫痫发生）决定了开发可以在早期阶段阻止癫痫过程的疗法的必要性。反过来，需要（a）与人类状况密切相似的实验模型的引入和验证，以及（b）允许对前瞻性抗癫痫药进行大规模筛查。当前的项目旨在引入和验证癫痫生成的动物模型，该模型可以大规模快速有效筛查新兴的抗癫痫药。