Prevention of Temporal Lobe Epilepsy

描述(申请人提供)：边缘癫痫是一种常见的、经常是破坏性的疾病，除了对少数患者进行手术外，没有预防或治愈的方法。 个人。癫痫持续状态(SE)被认为是边缘癫痫发生发展过程中的一个重要病因事件。使用转基因小鼠进行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SE引起的自发性反复发作。我们发现了一种在体外和体内全身给药后限制TrkB信号的多肽。目的1确定该多肽的最佳药效和药代动力学特性的剂量和时间进程；在红藻氨酸诱导的SE诱导之前，小鼠将以不同的剂量和不同的间隔进行治疗。目的2将确定在红藻氨酸诱发的癫痫发作后40分钟开始用该肽治疗一周是否能防止癫痫诱发的自发性反复发作。这些目标的成功实现将为该多肽对SE诱发癫痫的疗效概念提供证据，并为UO1应用于该多肽的药理优化提供基础。

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.