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）：癫痫是一种重要的神经系统疾病，其特征是反复自发发作。据估计，超过230万美国人患有癫痫，每年有20万新的癫痫病例被诊断出来。癫痫是每年造成2.5万至5万名患者死亡的一个因素，估计每年造成125亿美元的损失。因此，癫痫对美国公众来说是一个主要的经济和个人负担。不幸的是，抗癫痫药物（AEDs）对大约30%的患者无效。治疗往往伴随着不良副作用，这可能是由于aed影响了癫痫发作区以外的目标区域。为了开发更有效、副作用更少的治疗方法，人们一直在努力了解癫痫中神经元过度兴奋的潜在机制。在慢性癫痫中，分子和细胞变化发生在癫痫发作区，使其能够产生自发癫痫发作。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，将极大地有助于开发针对癫痫病因的新疗法。在这个提议中，我们将研究钠（Na）通道在癫痫发生中的变化。钠通道在控制神经元兴奋性中起着至关重要的作用，因此，钠通道阈值和放电模式的变化将对系统的兴奋性产生重大影响。钠通道突变导致的钠通道行为的改变是许多遗传性全身性癫痫的原因。我们的中心假设是，使神经元更容易兴奋的钠通道的表达和生理变化广泛存在于边缘系统癫痫发作区。为了支持这些变化有助于癫痫发展的假设，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后果。我们的建议将集中在内侧内鼻皮层（mEC）和下带神经元使用颞叶癫痫（TLE）的动物模型，成人药物抵抗癫痫的一种常见形式。我们提供的初步数据表明，癫痫动物的mEC第II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。这些发现支持了我们的中心假设，即钠通道的表达和生理变化有助于癫痫的发展。