Gamma-ketoaldehydes in epileptogenesis

γ-酮醛在癫痫发生中的作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由适用提供）：颞叶癫痫（TLE）是一种普遍的，通常是耐药性癫痫的耐药形式，经常出现诸如认知功能障碍之类的合并症。在包括TLE实验模型在内的各种神经系统疾病中，氧化应激已被暗示。但是，氧化应激是否有助于慢性癫痫发作和/或TLE认知能力下降。 Isoketals（Isoks）和神经母体（神经龙）是高度反应性的γ-酮醛（γkas），该醛（γkas）通过非酶的，自由基的自由基催化，蛛网膜烯酸和莫萨六烯酸的过氧化分别在脑中高度富集。 γkas迅速，不可逆转地加入赖氨酸保留率，并容易地交联蛋白，这会导致细胞功能障碍。血浆中的ISOK升高，组织发生在包括阿尔茨海默氏病，动脉粥样硬化和炎症的病理状况下。已经证明对γKA的药理清除可显着抑制人源化APOE4小鼠的认知障碍，这是阿尔茨海默氏病的动物模型。该项目的目标是1）确定在癫痫发生期间是否发生ISOK和/或神经加合物形成，2）确定候选的候选海马蛋白在癫痫发生过程中使用ISOKS/神经神经化的加合物加合物，3）是否与γKAS的药物清晰（SA）相关性或相关性。 4）确定SA是否可以抑制与癫痫发生相关的神经元死亡和/或反应性神经胶质变性。总的来说，该项目可以识别γkas作为氧化应激的介体在慢性癫痫发生和/或认知中的新作用。与TLE相关的损害，并为其治疗提供了一种治疗方法。