Development of Novel Antiepileptic Drugs

描述(申请人提供)：癫痫，一种神经疾病，是一个重大的公共卫生问题，影响着超过200万美国人。每年新诊断的癫痫病例超过10万例。目前对癫痫发作患者的治疗包括用抗癫痫药物(AEDs)抑制这些发作。由于钠通道控制细胞的兴奋性，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AEDs将钠通道作为其作用的主要机制。然而，继续推出新的AEDs并没有帮助大约75万对当前药物产生抗药性的美国人。此外，许多药物可控制癫痫发作，但代价是产生明显的毒副作用。这一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的“癫痫”神经元中存在的病理情况。例如，研究表明，在动物和人类边缘癫痫中，钠通道亚型的表达以及它们的活动/门控都会发生变化。这些变化与参与边缘癫痫的神经元的高兴奋性有关，也与颞叶癫痫的药理学改变有关，从而降低了钠通道阻滞剂抑制癫痫发作的效果。这些观察结果强调了开发代表“癫痫”状态而不是对照的“非癫痫”状态的筛查分析的重要必要性。开发这样一种筛查的直接结果将是确定对治疗耐药患者有效的候选疗法。在这项探索性/发展性翻译方案中，我们计划利用从慢性边缘癫痫(CLE)动物中分离出的神经元来开发一种“癫痫”筛查模式。我们将使用临床上使用的以钠通道为靶点的AEDs和一系列选择性钠通道阻滞剂来开发电生理筛查方案，这些药物对钠通道异构体具有不同的疗效。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大鼠是一种药物耐药癫痫伴自发发作的模型。这项建议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一种电生理筛选试验，使我们能够对候选疗法进行初步筛选；2)它将提供关于候选疗法疗效的初步数据，从而确定可以通过进一步的临床前试验进行评估的候选疗法。具体地说，我们计划：1)开发一个使用“癫痫”脑片的候选治疗药物的电生理学筛选配置文件--识别候选治疗药物。2)慢性边缘癫痫动物模型中抗惊厥活性候选治疗药物的临床前测试--电生理学筛查的验证。 公共卫生相关性：癫痫是一种神经疾病，是影响200多万美国人的主要公共卫生问题。大约75万美国人经历了现有药物无法抑制的癫痫发作。患者继续经历无法控制的、危及生命的癫痫发作。在这一探索性/发展计划中，我们将开发一种药物测试屏幕，以识别对癫痫神经元有效的药物。这些药物可能对对现有药物具有“耐药性”的患者有效。

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.