The metabolome of epileptic seizures

描述（由申请人提供）：本申请的长期目标是了解癫痫的化学机制，以便：(a)发现新的治疗靶点，更有效地预防癫痫发作，副作用更少，(b)在癫痫发作前几小时建立预测的生物标志物。这一目标与NINDS实现真正治愈癫痫的规划相一致，该规划的定义是“无癫痫发作，无副作用”。本文的目的是在实验室模型中对自发性癫痫发作的化学特征（代谢组）进行全面研究，内侧颞叶癫痫是最常见的耐药癫痫之一。核心假设是癫痫发作具有独特的化学特征，包括癫痫发作前自然发生的化学物质和大脑代谢途径的变化。据推测，这些变化可以作为新的治疗靶点和预测癫痫发作的生物标志物。为了实现这一应用的目的，将通过体内微透析和毛细管采血对实验室模型中内侧颞叶癫痫的脑和血液化学进行取样，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（代谢组学）方法确定。化学剖面将与电生理数据相关联，特别是癫痫发作的发生，使用连续的颅内脑电图（EEG）记录。初步研究表明，这种方法可以在几天内检测和量化1000多种不同小分子（< 1000 Da）化学物质的小时变化。同样的研究表明，在癫痫发作前几小时，某些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.