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: 8293932
• 负责人: MANOJ K PATEL
• 金额: $ 33.69万
• 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/8293932
• 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 Delivery Systems; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Epilepsy is a neurological disorder and is a major public health issue affecting over 2 million Americans. Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy that is difficult to treat pharmacologically. The limbic system is known to be heavily implicated in seizure generation in TLE. In this proposal we will determine the changes in sodium channel activity within the limbic system during the development of epileptic seizures in an animal model of TLE. Since Na channels are the target for many clinically used anticonvulsant drugs a better understanding of the importance of Na channels in epileptogenesis could provide a target for therapy development.

描述（由申请人提供）：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。据估计，超过 230 万美国人患有癫痫症，每年诊断出 20 万例新癫痫病例。癫痫每年导致 25,000 至 50,000 名患者死亡，估计每年造成 125 亿美元的损失。因此，癫痫是美国公众的主要经济和个人负担。不幸的是，抗癫痫药物 (AED) 对大约 30% 的患者无效。治疗常常与不良副作用相关，这可能是 AED 影响癫痫发作区以外区域的目标的结果。为了开发更有效、副作用更少的治疗方法，人们齐心协力去了解癫痫中神经元变得过度兴奋的潜在机制。在慢性癫痫中，癫痫发作区域内发生分子和细胞变化，使其能够产生自发性癫痫发作。很明显，这些变化改变了药理学，因此通过识别癫痫发作区特有的重要变化，将极大有助于针对癫痫病因开发更具体的新疗法。 在本提案中，我们将研究癫痫发生过程中钠 (Na) 通道的变化。 Na通道在控制神经元兴奋性中发挥着关键作用，因此Na通道阈值和放电模式的变化将对系统兴奋性产生显着影响。众所周知，Na 通道突变导致的 Na 通道行为改变是多种遗传性全身性癫痫的原因。我们的中心假设是，在边缘系统癫痫发作区广泛发现 Na 通道的表达和生理学变化，使神经元更加兴奋。为了帮助支持这些变化导致癫痫发展的假设，有必要证明这些变化发生在自发性癫痫发作之前，因此不是癫痫发作的结果。我们的提案将重点使用颞叶癫痫（TLE）动物模型（成人耐药性癫痫的常见形式）来研究内侧内嗅皮层（mEC）和下托神经元。我们提供的初步数据表明，癫痫动物的 mEC 第二层神经元本质上是过度兴奋的，并且 Na 通道生理学也发生了改变。我们发现神经元兴奋性和钠离子通道行为的变化发生在自发性癫痫发作之前。这些发现支持我们的中心假设，即 Na 通道表达和生理学的变化有助于癫痫的发展。 公共卫生相关性：癫痫是一种神经系统疾病，也是影响超过 200 万美国人的主要公共卫生问题。颞叶癫痫（TLE）是成人癫痫最常见的形式，难以通过药物治疗。已知边缘系统与 TLE 癫痫发作密切相关。在本提案中，我们将确定 TLE 动物模型癫痫发作期间边缘系统内钠通道活性的变化。由于Na通道是许多临床使用的抗惊厥药物的靶点，更好地了解Na通道在癫痫发生中的重要性可以为治疗开发提供靶点。