Development of Novel Antiepileptic Drugs

描述（由申请人提供）：癫痫是一种神经系统疾病，是影响200多万美国人的重大公共卫生问题。每年确诊的癫痫新病例超过10万例。目前对癫痫发作患者的治疗包括使用抗癫痫药物（aed）抑制癫痫发作。由于钠通道控制细胞兴奋性，它们已成为抑制癫痫发作的重要靶点。事实上，许多临床使用的aed靶向钠通道作为其作用的主要机制。然而，持续引进新的aed并没有帮助估计有75万美国人对现有药物产生耐药性。此外，许多药物实现了癫痫的控制，但代价是产生了显著的毒副作用。造成这种不可接受的统计数据的一个潜在原因是，使用的筛查不能代表患病“癫痫”神经元中存在的病理状况。例如，研究表明，在动物和人类边缘癫痫中，钠通道异构体表达及其活动/门控都会发生改变。这些变化与边缘癫痫中涉及的神经元的高度兴奋性以及在颞叶癫痫中已被充分记录的药理学改变有关，降低了钠通道阻滞剂抑制癫痫发作的功效。这些观察结果强调了开发代表“癫痫”状态而不是对照“非癫痫”状态的筛选分析的重要性。开发这种筛选的一个直接结果将是确定对治疗耐药患者有效的候选治疗方法。在这一探索性/发展性转化建议中，我们计划利用从慢性边缘癫痫（CLE）动物中分离的神经元开发一种“癫痫”筛查谱。我们将使用临床使用的aed（已知以钠通道为作用机制）和一系列选择性钠通道阻滞剂（对钠通道同种异构体具有不同的功效）开发电生理筛选概况。我们将通过评估CLE大鼠的抗惊厥活性来验证我们的筛选试验，CLE大鼠是一种自发发作的耐药癫痫模型。该提案将使我们能够确定两个重要特征：1)它将使我们能够开发和验证电生理筛选试验，从而允许对候选治疗方法进行初步筛选；2)它将提供候选治疗方法有效性的初步数据，从而确定候选治疗方法，并通过进一步的临床前测试进行评估。具体来说，我们计划：1)使用“癫痫”脑切片开发候选治疗方法的电生理学筛选概况-候选治疗方法的识别。慢性边缘癫痫动物模型抗惊厥活性候选疗法的临床前试验——电生理筛选的验证。

DESCRIPTION (provided by applicant): Epilepsy, a neurological disorder, is a major public health issue affecting over 2 million Americans. Each year over 100,000 new cases of epilepsy are diagnosed. Current treatment for patients suffering from epileptic seizures involves the suppression of these seizures with antiepileptic drugs (AEDs). Since sodium channels control cellular excitability, they have become important targets for the suppression of seizures. In fact, many of the clinically used AEDs target sodium channels as a major mechanism of their action. However, the continued introduction of new AEDs has not helped the estimated 750,000 Americans that are resistant to current drugs. In addition, many achieve seizure control but only at the cost of significant toxic side effects. One potential reason for this unacceptable statistic is the use of screens that are not representative of the pathological conditions that exist in a diseased "epileptic" neuron. For example, studies have shown that in both animal and human limbic epilepsy, alterations in sodium channel isoform expression as well as their activity/gating occurs. These changes have been associated with the hyper-excitability of neurons involved in limbic epilepsy and also the altered pharmacology that has been well documented in temporal lobe epilepsy, reducing the efficacy of the sodium channel blockers in suppressing epileptic seizures. These observations emphasize the important need to develop screening assays that represent the "epileptic" condition and not the control "non-epileptic" condition. A direct consequence of developing such a screen would be the identification of candidate therapeutics effective in therapy resistant patients. In this exploratory/developmental translational proposal we plan to develop an "epileptic" screening profile using neurons isolated from animals with chronic limbic epilepsy (CLE). We will develop an electrophysiology screening profile using clinically used AEDs, known to target sodium channels as a mechanism of action, and a series of selective sodium channel blockers that have a different efficacy profile against sodium channel isoforms. We will validate our screening assay by assessing anticonvulsant activity in CLE rats, a model of pharmacoresistant epilepsy with spontaneous seizures. This proposal will allow us to ascertain two important features 1) it will allow us to develop and validate an electrophysiology screening assay that will permit the preliminary screening of candidate therapeutics 2) it will provide preliminary data on the efficacy of candidate therapeutics leading to the identification of candidate therapeutics that can be evaluated through further preclinical testing. Specifically we plan to: 1) Develop an electrophysiology screening profile for candidate therapeutics using "epileptic" brain slices - identification of candidate therapeutics. 2) Pre-clinical testing of candidate therapeutics for anticonvulsant activity in an animal model of chronic limbic epilepsy - validation of the electrophysiology screen. Public Health Relevance: Epilepsy, a neurological disorder, is a major public health issue affecting over 2 million Americans. Approximately 750,000 Americans experience seizures that cannot be suppressed by currently available drugs. The patients continue to experience un-controlled, life threatening, epileptic seizures. In this exploratory/developmental proposal, we will develop a drug testing screen that will identify drugs that are effective in epileptic neurons. These drugs could be effective in patients that are "pharmaco-resistant" to currently available drugs.