Sodium channels and neuronal excitability in chronic limbic epilepsy.

慢性边缘癫痫的钠通道和神经元兴奋性。

• 批准号: 8412774
• 负责人: MANOJ K PATEL
• 金额: $ 32.51万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412774
• 关键词: Action Potentials; Adult; Adverse effects; Affect; American; Animal Model; Animals; Anticonvulsants; Antiepileptic Agents; Appearance; Axon; Back; Behavior; Cessation of life; Chronic; Data; Development; Diagnosis; Drug Targeting; Economics; Epilepsy; Epileptogenesis; Generalized Epilepsy; Generations; Inherited; Limbic System; Medial; Membrane; Molecular; Mutation; Neurons; Patients; Pattern; Pharmacology; Phosphorylation; Physiology; Play; Protein Isoforms; Public Health; RNA Interference; Recurrence; Resistance; Role; Seizures; Site; Sodium; Sodium Channel; System; Temporal Lobe Epilepsy; Testing; Up-Regulation; cost; density; effective therapy; entorhinal cortex; nervous system disorder; neuronal cell body; neuronal excitability; novel; therapy development

Epilepsy is a significant neurological disorder characterized by recurrent spontaneous seizures. It is estimated that over 2.3 million Americans have epilepsy with 200,000 new cases of epilepsy being diagnosed each year. Epilepsy is a factor in the deaths of between 25,000 to 50,000 patients each year and is estimated to cost the US $12.5 billion each year. Epilepsy therefore, is a major economic and personal burden for the American public. Unfortunately, antiepileptic drugs (AEDs) are ineffective in approximately 30% of patients. Too often treatment is associated with adverse side effects which may be the result of the AEDs affecting their targets in regions outside the seizure onset zone. In order to develop more effective treatments with fewer side effects there has been a concerted effort to understand the underlying mechanisms by which neurons become hyperexcitable in epilepsy. In chronic epilepsy molecular and cellular changes occur within the seizure onset zone, making it capable of generating spontaneous seizures. It has become clear that these changes have an altered pharmacology so that the development of new therapies that are more specific for the causes of epilepsy will be greatly aided by identifying important changes that are unique to the seizure onset zone. In this proposal we will examine the changes in sodium (Na) channels in epileptogenesis. Na channels play a critical role in controlling neuronal excitability, and so changes in Na channel thresholds and firing patterns would have significant effects on system excitability. Alterations in Na channel behavior, as a result of Na channel mutations, are known to be responsible for a number of inherited forms of generalized epilepsy. Our central hypothesis is that alterations in the expression and physiology of Na channels that make neurons more excitable are found broadly in the limbic system seizure onset zone. To help support the hypothesis that these changes contribute to the development of epilepsy it is necessary to show that the changes occur before the onset of spontaneous seizures and are thus not a consequence of the seizures. Our proposal will focus on medial entorhinal cortex (mEC) and subiculum neurons using an animal model of temporal lobe epilepsy (TLE), a common form of adult pharmaco-resistant epilepsy. We provide preliminary data demonstrating that mEC layer II neurons are intrinsically hyperexcitable in epileptic animals and that Na channel physiology is also altered. We show that changes in neuronal excitability and Na channel behavior occur before the appearance of spontaneous seizures. These findings support our central hypothesis that changes in Na channel expression and physiology contribute to the development of epilepsy.

癫痫是一种重大的神经系统疾病，其特征是复发性自发癫痫发作。这是 据估计，超过230万美国人患有癫痫病，被诊断为200,000例新病例 每年。癫痫是每年25,000至50,000名患者死亡的一个因素，估计为 每年花费125亿美元。因此，癫痫是对 美国公众。不幸的是，大约30％的患者在大约30％的患者中无效。也 治疗通常与不良副作用有关，这可能是AED影响其的结果 癫痫发作区以外地区的目标。为了开发更有效的治疗方案 效果一直在努力理解神经元变成的潜在机制 癫痫发作过度。在慢性癫痫分子和细胞变化中，发生在癫痫发作中 区域，使其能够产生自发癫痫发作。很明显，这些变化有一个 改变药理学，以使新疗法的开发更具体地是针对的原因 通过确定癫痫发作区域所特有的重要变化，癫痫将得到极大的帮助。 在此提案中，我们将检查癫痫生成中钠（NA）通道的变化。 NA通道 在控制神经元兴奋性方面发挥着关键作用，因此NA通道阈值的变化和触发 模式将对系统兴奋性产生重大影响。 NA通道行为的改变，由于 已知NA通道突变负责多种遗传形式的广义癫痫。我们的 中心假设是使神经元更多的NA通道的表达和生理学改变 在边缘系统癫痫发作区域中广泛发现了可兴奋的。为了帮助支持这些假设 变化有助于癫痫的发展，有必要证明这些变化发生在 自发发作的发作，因此不是癫痫发作的结果。我们的建议将重点放在 使用颞叶癫痫（TLE）的动物模型，内侧肠系膜（MEC）和下膜神经元， 成人抗药性癫痫的一种常见形式。我们提供初步数据，证明MEC 第二层神经元在癫痫动物中本质上是过度过度的，并且NA通道生理学也是 改变。我们表明，在出现之前，神经元兴奋性和NA通道行为发生变化 自发癫痫发作。这些发现支持我们的中心假设，即NA通道表达的变化 生理学有助于癫痫的发展。