Kynurenines, Glia and Epilepsy

犬尿氨酸、神经胶质细胞和癫痫

• 批准号: 6763219
• 负责人: ROBERT SCHWARCZ
• 金额: $ 35.74万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763219
• 关键词: NMDA receptors; acetylcholine; aminoacid metabolism; astrocytes; brain electrical activity; brain metabolism; disease /disorder model; electrophysiology; entorhinal cortex; epilepsy; experimental brain lesion; glia; kynurenate; kynurenine; laboratory rat; neural degeneration; neuropharmacology; neurotransmitter receptor; partial seizure; pathologic process; temporal lobe /cortex disorder; tissue /cell culture

DESCRIPTION (provided by applicant): Nerve cell death and gliosis in the limbic system are neuropathological hallmarks of temporal lobe epilepsy (TLE). This neuronal loss is initially caused by prolonged seizure activity and eventually results in recurrent, spontaneous seizures, i.e. chronic epilepsy. The mechanisms responsible for chronic epilepsy have been central themes of this project for many years. The proposed studies build on a concept that was developed during the past grant period. These data suggest that kynurenic acid (KYNA), an astrocyte-derived, endogenous antagonist of N-methyl-D-aspartate (NMDA) and alpha7 nicotinic acetylcholine (alpha7 nACh) receptors, is an anti-epileptic factor that is particularly effective in the entorhinal cortex (EC), a limbic brain region that is increasingly recognized as a "hot spot" in TLE. Up-regulation of brain KYNA levels results in a substantial reduction in seizure frequency in chronically epileptic rats. The planned studies will examine the role of KYNA in chronic epilepsy, using electrophysiological and biochemical methods in vivo and in vitro. In addition, novel pharmacological agents that use astrocytes for the focal delivery of KYNA will be examined. Two established rat models of chronic epilepsy will be used for hypothesis testing. Specific Aim 1 will test the hypothesis that an increase in the endogenous production of KYNA significantly reduces seizure frequency in animals exhibiting recurrent, spontaneous seizures. These in vivo studies will also evaluate whether the anti-epileptic efficacy of elevated KYNA is caused by an action at both NMDA and alpha7 nACh receptors, and whether KYNA preferentially targets the EC to effect seizure reduction; Specific Aim 2 will assess the regulation of cerebral KYNA in epileptic tissue in vitro. The regulatory mechanisms that normally control brain kynurenine pathway metabolism and function are impaired in chronic epilepsy. These studies are designed to uncover the cellular and molecular mechanisms that account for abnormal KYNA formation in epileptic tissue; Specific Aim 3 will examine the role of KYNA in epileptogenesis and epilepsy by electrophysiological means in vitro. Combined extracellular and intracellular recordings will be used to reveal the mechanisms underlying the hyperexcitability of entorhinal neurons, and the reason for their exquisite sensitivity to KYNA, in chronic epilepsy. Taken together, these studies will a) provide a comprehensive assessment of the role of KYNA in chronic epilepsy; b) contribute to our understanding of the role of the EC in chronic seizure phenomena and c) introduce a new therapeutic strategy which may offer advantages for the treatment of TLE.

描述（由申请人提供）：边缘系统中的神经细胞死亡和神经病是颞叶癫痫（TLE）的神经病理学标志。这种神经元丧失最初是由长时间的癫痫发作引起的，最终导致自发性癫痫发作，即慢性癫痫。多年来，负责慢性癫痫的机制一直是该项目的中心主题。拟议的研究基于过去赠款​​期间开发的概念。这些数据表明，金素酸（Kyna）是一种星形胶质细胞衍生的，内源性的内源性拮抗剂（NMDA）（NMDA）和α7烟碱乙酰胆碱（Alpha7 nach）受体，是一种抗肌动物因素，是一种抗肌动物，是eNtorex cotore conterex（ecortial cortore conterex）（ecortial contiment of insex contore）（ecortex contiment insex）（ecortex）（ecortex ecortex）（ecortex）（ecortex），这是一种limbic（ecortial contore）（ecortex ecortex nimbic）。在TLE中。脑kyna水平的上调导致长期癫痫大鼠的癫痫发作频率大大降低。计划的研究将使用体内和体外的电生理和生化方法来检查Kyna在慢性癫痫中的作用。此外，将检查使用星形胶质细胞进行Kyna焦点递送的新型药理学剂。两种已建立的大鼠模型的慢性癫痫模型将用于假设检验。具体目标1将检验以下假设：Kyna内源性产生的增加可显着降低表现出自发性癫痫发作的动物的癫痫发作频率。这些体内研究还将评估Kyna升高的抗癫痫功效是否是由NMDA和Alpha7 NACH受体的作用引起的，以及Kyna是否优先针对EC靶向EC的作用。具体目标2将评估体外癫痫组织中脑kyna的调节。慢性癫痫病中通常控制脑kynurenine途径的代谢和功能的调节机制受损。这些研究旨在发现癫痫组织中kyna异常形成的细胞和分子机制。特定的目标3将检查Kyna在体外电生理方法中的癫痫生成和癫痫癫痫的作用。结合细胞外和细胞内记录将用于揭示内嗅神经元过度兴奋性的基础机制，以及它们在慢性癫痫中对Kyna敏感的原因。综上所述，这些研究将a）对Kyna在慢性癫痫中的作用进行全面评估； b）有助于我们理解EC在慢性癫痫发作现象中的作用，c）引入了一种新的治疗策略，该策略可能为治疗TLE提供优势。