The role of oxidative stress and inflammation in epileptogenesis

总结 癫痫综合征及其潜在的病理生理学的巨大异质性代表了一个特殊的 对癫痫预防途径特异性疗法的发展提出了挑战。在许多人中，癫痫 是由特定的大脑“损伤”产生的，如创伤、梗塞或长时间癫痫持续状态发作 (SE)而在其他人中，癫痫是原发性遗传异常的结果， 发育中大脑的功能改变在所有情况下，患者都有患癫痫的高风险。 过去十年的研究表明，氧化应激， 炎症和癫痫，使得癫痫发作可以诱导氧化应激和炎症，而且， 大脑中的氧化应激和增强的促炎信号有助于癫痫的进展。最近 动物和人类研究已经确定了一种潜在的新靶点，其可能是 核因子红细胞2相关因子2（Nrf2）。该转录因子 促进多种保护性抗氧化和抗炎蛋白的表达。主要目的 本项目的目的是确定富马酸二甲酯（DMF），一种独特的减少氧化的Nrf2诱导剂， 压力和炎症，并被批准用于其他临床适应症，可以预防癫痫在两个不同的 小鼠癫痫模型。为了增加我们研究的转化潜力，我们还将确定 选择氧化应激和炎症的全身性生物标志物是否能够预测 癫痫和癫痫相关的共病（预后生物标志物），并监测急性反应， 治疗（药效学生物标志物）。Aim 1将使用癫痫发作的长期视频EEG记录， 行为测试，以确定在诱导SE后给予DMF是否会降低 癫痫的发病率和严重程度，并减少相关的行为合并症。使用 免疫组织化学和生物化学方法，目标2将评估与氧化还原相关的蛋白质的变化 在相同条件下，DMF处理后脑和血浆中的炎症和细胞因子信号传导 模型，假设与疾病进展最密切相关的介质将更多 而不是那些没有受到治疗的人。最后，为了检验是否有更普遍的 在目标3中，我们将确定DMF是否可以预防或延迟 癫痫和认知功能障碍的结节性硬化模型中癫痫的发展。

SUMMARY The large heterogeneity of epileptic syndromes and their underlying pathophysiology represent a particular challenge to the development of pathway-specific therapies for epilepsy prevention. In many people, epilepsy is produced by specific brain “insults”, such as trauma, infarcts, or episodes of prolonged status epilepticus (SE), while in others, epilepsy is a result of a primary genetic abnormality producing either structural or functional alterations in the developing brain. In all cases, patients are at high risk for developing epilepsy. Studies in the last decade have contributed to the view that there is an important link between oxidative stress, inflammation and epilepsy, such that seizures can induce oxidative stress and inflammation, but also that oxidative stress and enhanced pro-inflammatory signals in the brain contribute to epilepsy progression. Recent animal and human studies have identified a potential novel target that may be a central component of a cascade of such processes - the nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor promotes the expression of multiple protective antioxidant and anti-inflammatory proteins. The major objective of this project is to determine whether dimethyl fumarate (DMF), a Nrf2 inducer that uniquely reduces oxidative stress and inflammation and is approved for other clinical indications, can prevent epilepsy in two distinct mouse models of epileptogenesis. To increase the translational potential of our study, we will also determine whether select systemic biomarkers of oxidative stress and inflammation are able to predict the development of epilepsy and epilepsy-associated co-morbidities (prognostic biomarkers) and monitor the acute response to treatment (pharmacodynamic biomarkers). Aim 1 will use long-term video EEG recordings of seizures and behavioral testing to determine whether DMF, when administered following induction of SE, will reduce the incidence and severity of epilepsy and reduce the associated behavioral comorbidities. Using immunohistochemical and biochemical methods, Aim 2 will assess changes in proteins associated with redox modulation, inflammation and cytokine signaling in the brain and plasma following DMF treatment in the same model, with the hypothesis that mediators that most strongly associate with disease progression will be more affected by treatment than the ones that are not. Finally, to examine whether there is more generalizable applicability of this drug to other epilepsies, in Aim 3 we will determine whether DMF can prevent or delay the development of epilepsy in a tuberous sclerosis model of epilepsy and cognitive dysfunction.