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）：边缘癫痫是一种常见且经常具有破坏性的疾病，除了少数患者的手术外，没有预防或治愈方法。 个体癫痫持续状态（SE）已被认为是边缘系统癫痫发生的关键病因学事件。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的活化将阻止转基因小鼠的发展。 由于边缘系统SE引起的自发性复发性癫痫发作。我们已经发现了一种肽，其在体外和体内全身施用后限制TrkB信号传导。目的1将确定该肽的功效和药代动力学性质的最佳剂量和时程;在诱导红藻氨酸诱导的SE之前，将用不同剂量和以不同间隔处理小鼠。目的2将确定在红藻氨酸诱发的SE发作后40分钟开始用肽治疗一周是否会预防SE诱发的自发复发性癫痫发作。这些目标的成功完成将提供该肽对SE诱导的癫痫发生的有效性的概念证明，并提供旨在对该肽进行药理学优化的UO 1应用的基础。