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: 8601912
• 负责人: MANOJ K PATEL
• 金额: $ 33.35万
• 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/8601912
• 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.

癫痫是一种严重的神经系统疾病，其特征是反复自发性癫痫发作。这是 据估计，超过 230 万美国人患有癫痫症，新诊断的癫痫病例达 20 万例 每年。癫痫每年导致 25,000 至 50,000 名患者死亡，据估计 每年花费 125 亿美元。因此，癫痫是一个重大的经济和个人负担 美国公众。不幸的是，抗癫痫药物 (AED) 对大约 30% 的患者无效。也 治疗常常与不良副作用相关，这可能是 AED 影响其疗效的结果 癫痫发作区以外区域的目标。为了开发出更有效、更少副作用的治疗方法 人们一致努力去了解神经元变成的潜在机制 癫痫患者过度兴奋。在慢性癫痫中，癫痫发作时会发生分子和细胞变化 区，使其能够产生自发性癫痫发作。很明显，这些变化具有 改变药理学，以便开发出更针对病因的新疗法 识别癫痫发作区特有的重要变化将极大地帮助癫痫治疗。 在本提案中，我们将研究癫痫发生过程中钠 (Na) 通道的变化。钠通道 在控制神经元兴奋性中发挥关键作用，因此钠通道阈值和放电的变化 模式会对系统的兴奋性产生重大影响。 Na 通道行为的改变，由于 众所周知，Na 通道突变是导致多种遗传性全身性癫痫的原因。我们的 中心假设是 Na 通道表达和生理学的改变使神经元更加活跃 兴奋性广泛存在于边缘系统癫痫发作区。为了帮助支持这些假设 变化会导致癫痫的发展，有必要证明这些变化发生在癫痫发作之前。 自发性癫痫发作，因此不是癫痫发作的结果。我们的建议将集中于 使用颞叶癫痫（TLE）动物模型的内侧内嗅皮层（mEC）和下托神经元， 成人耐药性癫痫的常见形式。我们提供初步数据证明 mEC 在癫痫动物中，第二层神经元本质上是高度兴奋的，Na 通道的生理学也是如此 改变了。我们发现神经元兴奋性和Na通道行为的变化发生在出现之前 自发性癫痫发作。这些发现支持我们的中心假设，即 Na 通道表达的变化 和生理学有助于癫痫的发展。