Gamma-ketoaldehydes in epileptogenesis

γ-酮醛在癫痫发生中的作用

• 批准号: 8657371
• 负责人: MANISHA N PATEL
• 金额: $ 35.12万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657371
• 关键词: Alzheimer' s Disease; Animal Model; Antiepileptogenic; Arachidonic Acids; Area; Atherosclerosis; Attenuated; Behavioral; Benchmarking; Biochemical; Brain; Brain Injuries; Cells; Cessation of life; Chronic; Cognitive; Cognitive deficits; Development; Disease; Docosahexaenoic Acids; Drug resistance; Electroencephalography; Epilepsy; Epileptogenesis; Exhibits; Experimental Models; F2-Isoprostanes; Free Radicals; Functional disorder; Gliosis; Goals; Hippocampal Formation; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; Impairment; Inflammation; Injury; Isoprostanes; Lead; Learning; Lipid Peroxidation; Lysine; Mass Spectrum Analysis; Mediator of activation protein; Memory; Memory impairment; Modeling; Mus; Neuroglia; Neurons; Oxidants; Oxidative Stress; Pathway interactions; Performance; Plasma; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Proteins; Qualitative Methods; Quality of life; Recurrence; Reporting; Research; Role; SCN1A protein; Seizures; Site; Temporal Lobe Epilepsy; Therapeutic; Tissues; United States National Institutes of Health; Work; adduct; apolipoprotein E-4; astrogliosis; comorbidity; kainate; ketoaldehyde; morris water maze; nervous system disorder; neuronal excitability; novel; object recognition; peroxidation; prevent; protein crosslink; public health relevance; tau Proteins

ABSTRACT Temporal lobe epilepsy (TLE) is a prevalent, often drug resistant form of acquired epilepsy that frequently presents with co-morbidities such as cognitive dysfunction. Oxidative stress has been implicated in various neurological diseases including experimental models of TLE. However, whether oxidative stress contributes to chronic seizures and/or cognitive decline in TLE is unknown. Isoketals (IsoKs) and neuroketals (NeuroKs) are highly reactive gamma-ketoaldehydes (¿KAs) formed via the non-enzymatic, free radical catalyzed, peroxidation of arachidonic acid and docosahexaenoic acid, respectively which are highly enriched in brain. ¿KAs rapidly and irreversibly adduct to lysine residues and readily crosslink proteins which can lead to cell dysfunction. Elevated IsoKs in plasma and tissues occur in pathological conditions including Alzheimer's disease, atherosclerosis, and inflammation. Pharmacological scavenging of ¿KAs has been shown to markedly inhibit cognitive impairment in humanized apoE4 mice, an animal model of Alzheimer's disease. The goals of this project are to 1) determine whether IsoK and/or NeuroK adduct formation occurs during epileptogenesis, 2) Identify candidate hippocampal proteins adducted by IsoKs/NeuroKs using mass spectrometry during epileptogenesis, 3) determine if a pharmacological scavenger of ¿KAs, salicylamine (SA) can inhibit cognitive decline and/or chronic seizures associated with epileptogenesis and 4) determine if SA can inhibit neuronal death and/or reactive gliosis associated with epileptogenesis. Collectively, this project can identify a novel role of ¿KAs as mediators of oxidative stress in chronic epilepsy and/or cognitive impairment associated with TLE and provides a therapeutic approach for its treatment.

摘要 颞叶癫痫（TLE）是一种常见的获得性癫痫，通常具有耐药性， 出现认知功能障碍等并发症氧化应激与多种 神经系统疾病，包括TLE的实验模型。然而，氧化应激是否有助于 TLE中的慢性癫痫发作和/或认知下降尚不清楚。异缩酮（IsoKs）和神经缩酮（NeuroKs）是 通过非酶促、自由基催化， 花生四烯酸和二十二碳六烯酸的过氧化，它们分别在脑中高度富集。 KA快速和不可逆地加合到赖氨酸残基上，并容易交联蛋白质，从而导致细胞凋亡。 功能障碍血浆和组织中IsoKs的升高发生在包括阿尔茨海默氏症在内的病理条件下 疾病、动脉粥样硬化和炎症。药理学清除的钾已被证明显着 抑制人源化apoE 4小鼠（一种阿尔茨海默病动物模型）中认知障碍。的目标 该项目是1）确定IsoK和/或NeuroK加合物的形成是否发生在癫痫发生过程中，2） 使用质谱法鉴定IsoKs/NeuroKs加合的候选海马蛋白， 癫痫发生，3）确定药物清除剂的<$KA，水杨胺（SA）是否可以抑制认知 下降和/或慢性癫痫发作与癫痫发生和4）确定是否SA可以抑制神经元 死亡和/或与癫痫发生相关的反应性神经胶质增生。总的来说，这个项目可以确定一个新的角色， 在慢性癫痫和/或与TLE相关的认知障碍中，将KA作为氧化应激的介质 并提供了一种用于其治疗的治疗方法。