Redox Control of Seizure-Induced Neuroinflammation.

氧化还原控制癫痫引起的神经炎症。

基本信息

批准号：
10205182
负责人：
MANISHA N PATEL
金额：
$ 34.02万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205182
关键词：
Adverse effects Aging Antioxidants Arachidonic Acids Brain Cells Chronic Chronic Disease Cognition Cysteine Data Disease Epilepsy Erythroid Genetic Transcription Glutathione Glutathione Disulfide Goals Grant Human Impaired cognition Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Laboratories Lead Ligase Link Lipid Peroxidation Mediating Mediator of activation protein Methods Modeling Nuclear Oxidation-Reduction Oxidative Stress Process Production Rattus Reactive Oxygen Species Reduced Glutathione Role Seizures Series Signal Pathway Signal Transduction Status Epilepticus Sulforaphane Testing Therapeutic Intervention Tissues Up-Regulation Work acquired epilepsy base cell type cognitive function comorbidity cytokine improved in vivo neuroinflammation neuronal excitability novel novel therapeutics preservation prevent repaired synthetic enzyme targeted treatment therapeutic target

项目摘要

Inflammation and oxidative stress are two important processes known to occur concurrently in epilepsy. Neuroinflammation is a well-recognized mediator of acquired epilepsy and a highly investigated target for therapeutic intervention. Glutathione depletion occurs following insults that cause epilepsy and its repletion can modify seizures and cognitive impairment. Recent work in our laboratory has shown that elevation of glutathione can inhibit neuroflammation. The long term goal of this proposal is to elevate brain glutathione levels in models of acquired epilepsy by a novel mechanism i.e. direct posttranslational activation of its rate-limiting synthetic enzyme, - glutamyl cysteine ligase. The goal of this proposal is to test the hypothesis that increased de novo synthesis of glutathione decreases neuroinflammation, seizures and/or cognitive dysfunction. Aim. 1 will test select compounds for their ability to increase glutathione, inhibit neuroinflammation and neuronal excitability in vitro. Aim 2 will determine if compounds capable of elevating glutathione inhibit seizures, epilepsy and/or cognitive dysfunction. These studies can identify a novel mechanism of reducing neuroinflammation in acquired epilepsy and suggest redox-based compounds for the treatment of epilepsy and associated comorbidities.

炎症和氧化应激是已知同时发生的两个重要过程癫痫是公认的获得性癫痫的介质。研究的治疗干预目标是在损伤后发生谷胱甘肽耗竭。引起癫痫及其补充可以改变癫痫发作和认知障碍。我们的实验室表明，谷胱甘肽的升高可以长期抑制神经炎症。该提案的目标是提高获得性癫痫模型中的脑谷胱甘肽水平新机制，即其限速合成酶的直接翻译后激活，- 该提案的目标是检验从头增加的假设。谷胱甘肽的合成可减少神经炎症、癫痫发作和/或认知功能障碍。目标 1 将测试选定化合物增加谷胱甘肽、抑制神经炎症的能力。目标 2 将确定是否能够提高化合物的体外神经兴奋性。谷胱甘肽可抑制癫痫发作、癫痫和/或认知功能障碍。减少获得性癫痫神经炎症的新机制并建议基于氧化还原的用于治疗癫痫和相关合并症的化合物。