The metabolome of epileptic seizures

描述(申请人提供)：本申请的长期目标是了解癫痫的化学机制，以便：(A)发现更有效和副作用更少的新的治疗靶点，以及(B)在癫痫发作发生前几个小时建立预测生物标志物。这一目标与NINDS旨在真正治愈癫痫的计划是一致的，该计划被定义为“没有癫痫发作，没有副作用”。这里的目的是在内侧颞叶癫痫的实验室模型中对自发性癫痫的化学特征(代谢组)进行全面的研究，内侧颞叶癫痫是最常见的耐药癫痫形式之一。中心假设是癫痫发作有独特的化学特征，包括癫痫发作前大脑中自然产生的化学物质和代谢途径的变化。据推测，这些变化可以作为癫痫发作的新治疗靶点和预测生物标志物。为了实现这一应用的目的，将通过体内微透析和毛细血管血液采集几天来采集内侧颞叶癫痫实验室模型的脑和血液化学，直到癫痫发作被捕获。样品的综合化学成分将通过几种质谱学(代谢组学)方法确定。使用连续的视频-颅内脑电(EEG)记录，化学特征将与电生理数据，特别是癫痫的发生相关联。初步研究表明，这种方法可以在几天的时间内检测和量化1000多种不同小分子(&lt；1000 Da)化学物质的每小时变化。同样的研究表明，在癫痫发作发生前几个小时，特定化学物质的浓度会发生变化。

DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the chemical mechanism of epilepsy, in order to: (a) discover novel therapeutic targets that prevent seizures more efficiently and with fewer side effects, and (b) establish predictive biomarkers of impending seizures several hours before they occur. This objective is in line with NINDS' program towards real cures of epilepsy, defined as "no seizures, no side effects". The aim here is to perform a comprehensive study of the chemical profile (metabolome) of spontaneous seizures in a laboratory model of mesial temporal lobe epilepsy, which is one of the most common forms of drug-resistant epilepsies. The central hypothesis is that epileptic seizures have unique chemical signatures which include pre-seizure changes in naturally occurring chemicals and metabolic pathways in the brain. It is postulated that these changes can be exploited as novel therapeutic targets for and predictive biomarkers of epileptic seizures. To accomplish the objective of this application, the brain and blood chemistry in a laboratory model of mesial temporal lobe epilepsy will be sampled by in vivo microdialysis and capillary blood collections for several days, until epileptic seizures have been captured. The comprehensive chemical composition of the samples will be determined by several mass spectrometry (metabolomics) approaches. The chemical profile will be correlated with electrophysiological data, especially the occurrence of seizures, using continuous, video-intracranial electroencephalogram (EEG) recordings. Preliminary studies have shown that this approach can detect and quantify hourly changes in more than 1,000 different small molecule (<1,000 Da) chemicals over a period of several days. The same studies have indicated that specific chemicals change in concentration several hours before the occurrence of a seizure.