Redox Control of Seizure-Induced Neuroinflammation.

氧化还原控制癫痫引起的神经炎症。

• 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
• 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

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， 癫痫神经炎症是公认的获得性癫痫的介质， 研究治疗干预的目标。谷氨酸盐耗竭发生在以下损伤， 引起癫痫及其饱食可以改变癫痫发作和认知障碍。最近的工作 我们的实验室已经表明谷胱甘肽的升高可以抑制神经炎症。长期 该提案的目的是通过以下方法提高获得性癫痫模型中的脑谷胱甘肽水平： 新的机制，即直接翻译后激活其限速合成酶， 谷氨酰半胱氨酸连接酶。这项提案的目的是检验增加从头开始的假设， 谷胱甘肽的合成减少神经炎症、癫痫发作和/或认知功能障碍。 瞄准1将测试选择化合物增加谷胱甘肽，抑制神经炎症 和体外神经元兴奋性。目标2将确定化合物是否能够提高 谷胱甘肽抑制癫痫发作、癫痫和/或认知功能障碍。这些研究可以确定一个 减少获得性癫痫中神经炎症的新机制，并建议基于氧化还原 用于治疗癫痫和相关合并症的化合物。