Gamma-ketoaldehydes in epileptogenesis

摘要 颞叶癫痫(TLE)是一种流行的、通常耐药的获得性癫痫形式，经常 存在认知功能障碍等共病。氧化应激与多种疾病有关 神经系统疾病，包括实验性的TLE模型。然而，氧化应激是否有助于 TLE的慢性癫痫发作和/或认知功能下降尚不清楚。异酮(IsoK)和神经酮(NeuroK)是 高活性的伽马-酮醛(？KAs)是通过非酶催化的自由基生成的， 花生四烯酸和二十二碳六烯酸的过氧化作用，这两种物质在大脑中高度丰富。 Kas迅速且不可逆转地与赖氨酸残基加成，并容易使蛋白质交联，从而导致细胞 功能障碍。血浆和组织中IsoKs的升高在包括阿尔茨海默氏症在内的病理条件下发生 疾病、动脉粥样硬化和炎症。Kas的药理清除作用已显示出明显的 抑制阿尔茨海默病动物模型--人源化apoE4小鼠的认知障碍。的目标 本项目旨在1)确定IsoK和/或NeuroK加合物是否在癫痫发生过程中形成，2) 质谱学方法鉴定IsoKs/NeuroKs加合物候选海马区蛋白 癫痫发生，3)确定Kas的药理清除剂水杨胺(SA)是否可以抑制认知 与癫痫发生相关的递减和/或慢性癫痫发作以及4)确定SA是否能抑制神经元 与癫痫发生相关的死亡和/或反应性胶质细胞增生症。总而言之，这个项目可以确定一个新的角色 在慢性癫痫和/或与TLE相关的认知损害中，Kas作为氧化应激的介质 并为其治疗提供了一种治疗方法。

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.