Gamma-ketoaldehydes in epileptogenesis

γ-酮醛在癫痫发生中的作用

• 批准号: 8737988
• 负责人: MANISHA N PATEL
• 金额: $ 33.7万
• 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/8737988
• 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; Comorbidity; 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; kainate; ketoaldehyde; morris water maze; nervous system disorder; neuronal excitability; novel; object recognition; peroxidation; prevent; protein crosslink; public health relevance; 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 (?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.

描述（由申请人提供）：颞叶癫痫（TLE）是一种常见的获得性癫痫，通常具有耐药性，经常伴有认知功能障碍等并发症。氧化应激与各种神经系统疾病有关，包括TLE的实验模型。然而，氧化应激是否有助于慢性癫痫发作和/或TLE认知能力下降尚不清楚。异缩酮（IsoKs）和神经缩酮（NeuroKs）是高反应性的γ-酮醛（？KA）分别通过花生四烯酸和二十二碳六烯酸的非酶促、自由基催化的过氧化作用形成，其在脑中高度富集。? KA快速且不可逆地加合至赖氨酸残基并容易交联蛋白质，这可导致细胞功能障碍。血浆和组织中升高的IsoK发生在包括阿尔茨海默病、动脉粥样硬化和炎症的病理状况中。药物清除？KA已显示出显著抑制人源化apoE 4小鼠（阿尔茨海默病的动物模型）中的认知障碍。本项目的目标是：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）确定候选海马蛋白加合的IsoKs/NeuroKs使用质谱在癫痫发生过程中，3）确定是否有药理学清道夫？KA，水杨胺（SA）可以抑制与癫痫发生相关的认知下降和/或慢性癫痫发作，以及4）确定SA是否可以抑制与癫痫发生相关的神经元死亡和/或反应性神经胶质增生。总的来说，这个项目可以确定一个新的作用？KA作为慢性癫痫和/或认知障碍患者氧化应激的介质 与TLE相关的损伤，并提供其治疗的治疗方法。