Peri-electrode large molecule microdialysis of the brain during induced seizures in mice, pigs, and humans with epilepsy undergoing resective surgery

对接受切除手术的癫痫小鼠、猪和人类诱发癫痫发作时进行大脑周围电极大分子微透析

• 批准号: 9753427
• 负责人: Charles Lee Howe
• 金额: $ 43.73万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2021-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753427
• 关键词: Acute; Affect; American; Animal Model; Autopsy; Brain; CCL2 gene; Caring; Characteristics; Chemicals; Chemotactic Factors; Choristoma; Chronic; Collection; Coupled; Development; Drug resistance; Effector Cell; Electrodes; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Event; Excision; Experimental Models; Extracellular Fluid; Failure; Family suidae; Functional disorder; Health; Hippocampus (Brain); Histology; Human; IL6 gene; Immune Targeting; In Situ; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Knowledge; Life; Link; Mass Spectrum Analysis; Measures; Medical; Membrane; Microdialysis; Mission; Modeling; Molecular; Molecular Weight; Monitor; Mus; Neurologic; Neurons; Nuclear Magnetic Resonance; Operative Surgical Procedures; Outcome Study; Pathogenesis; Pathology; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Probability; Production; Proteomics; Public Health; Recurrence; Refractory; Research; Role; Seizures; Serum; Site; Steroids; Synapses; TNF gene; Techniques; Testing; Therapeutic; Tissues; United States National Institutes of Health; Work; base; chemokine; cytokine; design; disability; experimental study; human study; immunomodulatory therapies; in vivo; innovation; insight; monocyte; mouse model; neural circuit; neuroinflammation; novel; patient population; personalized medicine; pre-clinical; recruit; relating to nervous system; release factor; response; screening; small molecule; success; targeted treatment; therapy resistant; translation to humans; treatment strategy

There is a critical unmet need to identify new strategies to control seizures in individuals with epilepsy who fail to respond to currently available drugs. Many of these individuals undergo invasive surgical resection of electroencephalographically aberrant tissue. However, seizures are likely to recur in up to half of these subjects within 5 years of surgery. Resistance to therapies that target electrophysiological mechanisms of aberrant neural activity coupled to post-surgical recurrence of seizures in previously non-ictal tissue may indicate a role for epileptogenic drivers that are non-neural and self-amplifying. Multiple studies have demonstrated changes in peripheral inflammatory factors in individuals with epilepsy, and steroids and other immunomodulatory therapies have proven effective in some patients. Likewise, evidence from animal models clearly supports a role for cytokines such as TNFα and IL1β in seizure activity. Therefore, neuroinflammation may be a critical driver of drug-resistant epilepsy. The central hypothesis of this proposal is that aberrant neural activity triggers local release of chemokines and cytokines that promote infiltration of innate inflammatory effector cells, production of additional inflammatory mediators, and further disruption of neural circuitry. Breaking this cycle may stop ictogenesis and/or epileptogenesis. The specific hypothesis of this proposal is that levels of the chemoattractant CCL2 and the effector cytokines TNFα, IL1β, and/or IL6 are elevated in spatial and temporal association with chemically induced epileptiform activity. This hypothesis will be tested using a strategy based on simultaneous collection of intracortical EEG activity and large molecule microdialysis to measure inflammatory mediators in the extracellular fluid of the peri-electrode space in mice and pigs and in humans undergoing resective surgery for drug-resistant epilepsy. Despite circumstantial evidence in humans indicating a role for inflammation in seizure disorders and epilepsy, no study has yet measured the in situ inflammatory characteristics of the epileptic brain or assessed the relationship between epileptiform activity and local release of inflammatory molecules. Though brain microdialysis has been established as a technique in the neurocritical care setting for assessment of small molecules, this study will be the first to employ an innovative strategy that combines intracranial EEG collection and the use of high molecular weight cut-off membranes (100 kDa) for the capture of chemokines and cytokines in the peri- electrode space. These experiments are significant as they will provide novel insights into the role of inflammatory mediators as both cause and effect of neural circuit dysfunction and they may identify individual inflammatory drivers that can be targeted for personalized treatment strategies. Regardless of outcomes, this study will generate new, fundamental knowledge about the interplay between seizure activity and inflammation. Understanding this relationship may provide support for the use of immunomodulatory therapies in the millions of individuals with epilepsy that are currently underserved by current standards of care.

对于失败的癫痫患者，迫切需要确定新的策略来控制癫痫发作 为了应对目前可用的药物，其中许多人接受了侵入性手术切除。 然而，其中多达一半的脑电图异常组织可能会复发。 手术后 5 年内对针对电生理机制的治疗产生耐药性。 异常的神经活动与先前非发作组织中癫痫发作的术后复发相结合可能 多项研究表明，非神经性和自我放大的致癫痫驱动因素具有一定的作用。 患有癫痫、类固醇和其他药物的个体外周炎症因子的变化 同样，来自动物模型的证据也证明免疫调节疗法对某些患者有效。 明确支持细胞因子如 TNFα 和 IL1β 在癫痫发作活动中的作用。 可能是耐药性癫痫的关键驱动因素 该提议的中心假设是异常。 神经活动触发趋化因子和细胞因子的局部释放，促进先天细胞的浸润 炎症效应细胞、额外炎症介质的产生以及神经系统的进一步破坏 打破这个循环可能会阻止癫痫发生和/或癫痫发生。 建议是化学引诱剂 CCL2 和效应细胞因子 TNFα、IL1β 和/或 IL6 的水平 该假设将在空间和时间上与化学诱发的癫痫样活动相关性升高。 使用基于同时收集皮质内脑电图活动和大分子的策略进行测试 微透析测量小鼠电极周围间隙细胞外液中的炎症介质 以及猪和接受耐药性癫痫切除手术的人类。 人类证据表明炎症在癫痫症和癫痫中发挥作用，但尚未有研究 测量癫痫脑的原位炎症特征或评估两者之间的关系 尽管脑微透析已被证实可导致癫痫样活动和炎症分子的局部释放。 作为神经重症监护环境中评估小分子的一项技术，这项研究将 第一个采用创新策略，结合颅内脑电图采集和高 分子量截止膜（100 kDa），用于捕获周围的趋化因子和细胞因子 这些实验非常重要，因为它们将为了解电极空间的作用提供新的见解。 炎症介质既是神经回路功能障碍的原因也是其影响，它们可以识别个体 无论结果如何，都可以针对炎症驱动因素进行个性化治疗策略。 研究将产生关于癫痫发作活动和炎症之间相互作用的新的基础知识。 了解这种关系可能为数百万人使用免疫调节疗法提供支持 目前的护理标准无法满足癫痫患者的需求。