Gamma-ketoaldehydes in epileptogenesis

描述(由申请人提供)：颞叶癫痫(TLE)是一种流行的获得性癫痫，通常具有抗药性，经常伴有认知功能障碍等共病。氧化应激与多种神经系统疾病有关，包括实验性的TLE模型。然而，氧化应激是否导致慢性癫痫发作和/或TLE认知功能下降尚不清楚。异酮类化合物(IsoKs)和神经酮类化合物(NeuroKs)是由脑内高度富含的花生四烯酸和二十二碳六烯酸分别在非酶催化、自由基催化、过氧化作用下形成的高活性伽马酮醛。？KA迅速和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。血浆和组织中的IsoKs升高发生在包括阿尔茨海默病、动脉粥样硬化和炎症在内的病理条件下。药物清除？Kas已被证明显著抑制人源化的apoE4小鼠的认知障碍，这是一种阿尔茨海默病的动物模型。该项目的目标是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)利用质谱学确定IsoKs/NeuroKs在癫痫发生过程中引用的候选海马蛋白，3)确定？Kas、水杨胺(SA)的药物清除剂是否可以抑制与癫痫发生相关的认知功能下降和/或慢性癫痫发作，以及4)确定SA是否可以抑制神经元死亡和/或与癫痫发生相关的反应性胶质增生。总而言之，该项目可以确定？Kas作为慢性癫痫和/或认知疾病中氧化应激的介体的新角色。 与TLE相关的损害，并为其治疗提供了一种治疗方法。

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.