Prevention of Temporal Lobe Epilepsy

颞叶癫痫的预防

• 批准号: 8430427
• 负责人: James O. McNamara
• 金额: $ 19.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430427
• 关键词: Adult; Amino Acids; Amygdaloid structure; Animal Model; Automobile Driving; Binding; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Clinical; Conscious; Development; Disease; Dose; Drug Kinetics; Electroencephalography; Employment; Enzyme Activation; Epilepsy; Epileptogenesis; Event; Half-Life; Hour; Human; In Vitro; Individual; Infusion procedures; Intervention; Kainic Acid; Kindling (Neurology); Mediating; Methods; Minority; Modeling; Molecular Target; Monitor; Mus; Mutant Strains Mice; Nervous System Physiology; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Operative Surgical Procedures; Pathogenesis; Penetration; Peptides; Phenylalanine; Phosphopeptides; Phosphorylation; Population; Prevention; Preventive; Property; Proteins; Receptor Protein-Tyrosine Kinases; Recurrence; Resistance; Rodent; Seizures; Signal Pathway; Signal Transduction; Status Epilepticus; Temporal Lobe Epilepsy; Testing; Time; Transgenic Organisms; Tyrosine; Vent; Viral; base; critical period; design; in vivo; insight; nervous system disorder; neurotrophic factor; overexpression; prevent; src Homology Region 2 Domain

DESCRIPTION (provided by applicant): Limbic epilepsy is a common and frequently devastating disorder for which there is no prevention or cure, except for surgery for a minority of individuals. Status epilepticus (SE) has been implicated as a key etiological event in development of limbic epilepsy. Studies of animal models using genetically modified mice suggest that limiting activation of the receptor tyrosine kinase, TrkB, will prevent development of spontaneous recurrent seizures arising as a consequence of limbic SE. We have discovered a peptide that limits TrkB signaling in vitro and following systemic administration in vivo. Aim 1 wil determine the optimal dose and time course of efficacy and pharmacokinetic properties of this peptide; mice will be treated with varying doses and at varying intervals prior to induction of kainic acid-induced SE. Aim 2 will determine whether one week of treatment with the peptide commencing 40 minutes after onset of kainic acid-evoked SE will prevent SE-induced spontaneous recurrent seizures. Successful completion of these Aims will provide proof of concept of efficacy of this peptide for SE-induced epileptogenesis and provide the basis of a UO1 application aimed at pharmacological optimization of this peptide.

描述（由申请人提供）：边缘性癫痫是一种常见且经常具有破坏性的疾病，除了少数患者进行手术外，没有任何预防或治愈方法。 个人。癫痫持续状态（SE）被认为是边缘叶癫痫发展的关键病因事件。使用转基因小鼠的动物模型研究表明，限制受体酪氨酸激酶 TrkB 的激活将阻止 边缘系统 SE 导致的自发性复发性癫痫发作。我们发现了一种在体外和体内全身给药后限制 TrkB 信号传导的肽。目标 1 将确定该肽的最佳剂量和疗效时程以及药代动力学特性；在诱导红藻氨酸诱导的 SE 之前，将以不同的剂量和不同的时间间隔对小鼠进行治疗。目标 2 将确定在红藻氨酸诱发的 SE 发作 40 分钟后开始使用该肽治疗一周是否可以预防 SE 诱发的自发性癫痫复发。这些目标的成功完成将为该肽对 SE 诱导的癫痫发生的功效提供概念证明，并为旨在优化该肽药理学的 UO1 应用提供基础。