Gamma-ketoaldehydes in epileptogenesis

γ-酮醛在癫痫发生中的作用

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

抽象的颞叶癫痫 (TLE) 是一种普遍存在且通常具有耐药性的获得性癫痫，存在认知功能障碍等并发症。然而，氧化应激会导致神经系统疾病，包括 TLE 实验模型。 TLE 中的慢性癫痫发作和/或认知能力下降尚不清楚。通过非酶、自由基催化形成的高反应性 γ-酮醛 (¿KA)，花生四烯酸和二十二碳六烯酸分别在大脑中高度丰富的过氧化。 ¿ KA 快速且不可逆地加成赖氨酸残基并容易交联蛋白质，从而导致细胞血浆和组织中的 IsoK 升高发生在包括阿尔茨海默病在内的病理情况下。疾病、动脉粥样硬化和炎症。 KA 已被证明可以显着抑制人源化 apoE4 小鼠（阿尔茨海默病动物模型）的认知障碍。该项目的目的是 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) 使用质谱法识别 IsoKs/NeuroKs 加合的候选海马蛋白癫痫发生，3) 确定 ¿ 的药理学清除剂KAs、水杨胺（SA）可以抑制认知癫痫发作相关的衰退和/或慢性癫痫发作，4) 确定 SA 是否可以抑制神经元总的来说，该项目可以确定与癫痫发生相关的死亡和/或反应性神经胶质增生。的 KA 作为慢性癫痫和/或 TLE 相关认知障碍中氧化应激的介质并为其治疗提供了治疗方法。