Gamma-ketoaldehydes in epileptogenesis

γ-酮醛在癫痫发生中的作用

• 批准号: 9096914
• 负责人: MANISHA N PATEL
• 金额: $ 34.11万
• 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 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096914
• 关键词: Alzheimer' s Disease; Animal Model; Antiepileptogenic; Arachidonic Acids; Area; Atherosclerosis; Attenuated; Behavioral; Benchmarking; Biochemical; Brain; Brain Injuries; Cells; Chronic; Cognitive; Cognitive deficits; Comorbidity; Development; Disease; Docosahexaenoic Acids; Drug resistance; Electroencephalography; Epilepsy; Epileptogenesis; Exhibits; Experimental Models; F2-Isoprostanes; Free Radicals; Functional disorder; Gliosis; Goals; Health; 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; kainate; ketoaldehyde; morris water maze; nervous system disorder; neuron loss; neuronal excitability; novel; object recognition; peroxidation; prevent; protein crosslink; spatial memory; targeted treatment; tau Proteins

DESCRIPTION (provided by applicant): 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 (γKAs) formed via the non-enzymatic, free radical catalyzed, peroxidation of arachidonic acid and docosahexaenoic acid, respectively which are highly enriched in brain. γKAs 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 γKAs 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 γKAs, 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 γKAs as mediators of oxidative stress in chronic epilepsy and/or cognitive impairment associated with TLE and provides a therapeutic approach for its treatment.

描述（由申请人提供）：颞叶癫痫（TLE）是一种常见的、通常具有耐药性的获得性癫痫，经常伴有认知功能障碍等合并症。氧化应激涉及多种神经系统疾病，包括TLE的实验模型。然而，氧化应激是否会导致TLE患者的慢性癫痫发作和/或认知能力下降尚不清楚。异ketals （IsoKs）和neuroketals （NeuroKs）分别是由花生四烯酸和二十二碳六烯酸的非酶自由基催化过氧化反应形成的高活性γ -酮醛（γ - kas），在大脑中含量很高。γ - kas可以快速不可逆地加合赖氨酸残基，并容易交联蛋白质，从而导致细胞功能障碍。血浆和组织中IsoKs的升高发生在病理条件下，包括阿尔茨海默病、动脉粥样硬化和炎症。γ - kas的药理清除已被证明能显著抑制人源化apoE4小鼠（阿尔茨海默病的动物模型）的认知障碍。该项目的目标是：1)确定在癫痫发生过程中是否发生IsoK和/或NeuroK加合物的形成；2)在癫痫发生过程中使用质谱法鉴定IsoK /NeuroK加合物的候选海马蛋白；水杨胺（SA）可以抑制与癫痫发生相关的认知能力下降和/或慢性癫痫发作；4)确定SA是否可以抑制与癫痫发生相关的神经元死亡和/或反应性神经胶质瘤。总的来说，该项目可以确定γ - kas作为慢性癫痫和/或认知氧化应激介质的新作用