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.

确定癫痫患者的癫痫发作的新策略是不满意的，失败的人 回应当前可用的药物。这些人中有许多接受了侵入性手术切除 脑电图异常的组织。但是，癫痫发作可能会在其中多达一半 手术5年内的受试者。抗靶向电生理机制的疗法 异常的神经元活性与以前非典型组织中癫痫发作后癫痫发作相结合可能 表明非神经和自我扩增的癫痫发作驱动因素的作用。多个研究有 证明了癫痫患者以及类固醇和其他人的外周炎症因子的变化 事实证明，免疫调节疗法对某些患者有效。同样，动物模型的证据 显然，在癫痫活性中的细胞因子（例如TNFα和IL1β）的作用。因此，神经炎症 可能是耐药性癫痫的关键驱动力。该提议的中心假设是异常 神经活动会触发趋势促进先天浸润的趋化因子和细胞因子的局部释放 炎性效应细胞，产生其他炎症介质以及进一步破坏神经 电路。打破此循环可能会阻止入口发生和/或癫痫发生。特定假设 提议是趋化剂CCL2和效应细胞因子TNFα，IL1β和/或IL6的水平是 在空间和临时关联中与化学诱导的癫痫样活性升高。这个假设将会 使用基于简单收集物质内脑电图活性和大分子的策略进行测试 微透析以测量小鼠周周外液体外流体中的炎症介质 和猪以及正在接受耐药性癫痫的切除手术的人。尽管间接 人类的证据表明炎症在癫痫发作和癫痫中的作用，尚无研究 测量了癫痫大脑的原位炎症特征或评估 癫痫样活性和炎症分子的局部释放。尽管大脑微透析一直是 本研究将作为用于评估小分子的神经严重护理环境中的技术，将是 第一个采用创新策略结合了颅内脑电图收集和使用高的策略 分子量截止膜（100 kDa），用于捕获趋化因子和细胞因子 电极空间。这些实验很重要，因为它们将提供有关其作用的新见解 炎症介体是神经回路功能障碍的因素和影响，它们可能会识别 可以针对个性化治疗策略的炎症驱动器。不管结果如何 研究将产生有关癫痫活性与炎症之间相互作用的新的基本知识。 了解这种关系可以为数百万的免疫调节疗法提供支持 目前按照当前护理标准的癫痫患者的服务不足。