The metabolome of epileptic seizures

癫痫发作的代谢组

• 批准号: 8659530
• 负责人: TORE EID
• 金额: $ 19.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659530
• 关键词: Adverse effects; Antiepileptic Agents; Appearance; Biological Markers; Blood; Blood Chemical Analysis; Blood capillaries; Brain; Brain Chemistry; Chemicals; Collection; Data; Development; Drug resistance; Early Diagnosis; Electroencephalogram; Environment; Epilepsy; Generations; Goals; Hour; Individual; Injury; Laboratories; Mass Spectrum Analysis; Metabolic Pathway; Methods; Microdialysis; Modeling; Monitor; National Institute of Neurological Disorders and Stroke; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Prevalence; Public Health; Rattus; Research; Sampling; Seizures; Stigmatization; Temporal Lobe Epilepsy; Testing; Unconscious State; Work; base; candidate identification; extracellular; improved; in vivo; in vivo Model; innovation; metabolomics; nervous system disorder; new therapeutic target; novel; peripheral blood; prevent; programs; public health relevance; small molecule; social

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.

描述（由申请人提供）：本申请的长期目的是了解癫痫的化学机制，以：（a）发现新型的治疗靶标，以防止癫痫发作更有效，副作用较少，并且（b）建立预测性生物标志物的预测性生物标志物在发生前几个小时。该目标与Ninds对癫痫的真实治疗的计划保持一致，该计划被定义为“无癫痫发作，无副作用”。这里的目的是对自发性癫痫发作的化学特征（代谢组）进行全面研究，这是颞颞叶癫痫的实验室模型，这是最常见的耐药性癫痫症的形式之一。中心假设是癫痫发作具有独特的化学特征，其中包括大脑中天然存在的化学物质和代谢途径的塞氏塞前变化。据推测，这些变化可以被用作癫痫发作的新型治疗靶标和预测生物标志物。为了实现此应用的目的，将在体内微透析和毛细血管血液收集中取样中颞叶癫痫的实验室模型中的大脑和血液化学，直到捕获癫痫发作。样品的综合化学组成将通过多种质谱法（代谢组学）方法确定。化学轮廓将与电生理数据相关，尤其是使用连续的视频脑电脑电脑图（EEG）记录的癫痫发作的发生。初步研究表明，这种方法可以在几天的时间内检测和量化1,000多个不同的小分子（<1,000个DA）化学物质的每小时变化。同样的研究表明，特定的化学物质在癫痫发作发生前几个小时的浓度变化。