Inhibition of Neural Electrode-mediated Inflammation and Neuronal Cell Death

 描述（由申请人提供）：神经电极介导的炎症和神经元细胞死亡的抑制正在开发越来越多的可植入神经电极装置，以绘制脑回路或恢复功能和治疗疾病。 这些器械的性能取决于电极-神经组织界面的质量和稳定性。 在动物研究中一直报告了不良脑组织反应，包括持续性小胶质细胞活化和血脑屏障破坏、胶质瘢痕形成、神经元损失和变性。 对于需要与宿主神经元密切接触的电极装置，其性能功能可能会受到这些响应的损害。 例如，通过微电极阵列的单个单元神经记录随着时间的推移在产量和质量上经历恶化，这是该技术在长期神经科学研究和临床转化中应用的主要障碍。 有许多分子和途径参与炎症和神经元死亡。 我们的研究开始于caspase-1，因为caspase-1是炎症和程序性细胞死亡的关键介质。 半胱天冬酶-1的激活是体外神经元凋亡和脑缺血、损伤和神经退行性疾病中最早可检测的事件。 此外，半胱天冬酶-1激活白细胞介素-1 β（IL-1 β），这是一种在植入电极周围组织中高度表达的促炎细胞因子，尤其是那些表现出不良电生理结果的组织。 IL-1 β触发炎性神经胶质增生并加剧BBB破坏;两者都是慢性记录失败的假设原因。 因此，我们假设半胱天冬酶-1介导神经元死亡和神经植入物周围的炎症，抑制半胱天冬酶-1可以改善神经元存活，减少炎症，并导致改善的电极性能。 我们进行了一项初步研究，比较植入caspase- 1敲除（KO）与野生型（WT）小鼠的微电极阵列的神经记录性能。 在6个月的时间段内，敲除动物的单个单位产量和信号质量显著更高，强烈支持胱天蛋白酶-1在维持电极-组织界面质量方面的关键作用。 然而，随着时间的推移，记录的更仔细的检查显示动态变化，不能解释与终点组织学。 为了更好地理解caspase-1介导的途径影响记录的机制，我们建议使用双光子活体动物成像来表征细胞和血管对植入神经探针的反应，并结合神经记录和全面的组织和生化分析。 一般将评价靶向半胱天冬酶-1或炎症/细胞死亡的治疗剂，以改善慢性神经界面。 待测试的药物是胱天蛋白酶1特异性抑制剂VX 765、褪黑激素和米诺环素。 该建议使用多学科的方法来揭示有助于神经记录性能的分子和细胞机制。 这些发现将增加我们对神经植入病理学的科学理解，并指导稳定可靠的神经界面的治疗和/或生物材料策略的发展。 该项目开发的数据和技术也可能有助于研究创伤性脑损伤、中风和神经退行性疾病中的神经元变性和炎症。

 DESCRIPTION (provided by applicant): Inhibition of Neural Electrode-mediated Inflammation and Neuronal Cell Death A growing number of implantable neural electrode devices are being developed to map brain circuit or restore function and treat diseases. The performance of these devices hinges on the quality and stability of the electrode-neural tissue interface. Undesirable brain tissue responses, including persistent microglia activation and blood brain barrier breach, glial scarring, neuronal loss and degeneration, have been consistently reported in animal studies. For electrode devices that require intimate contact with host neurons, their performance functionality may be compromised by these responses. As an example, single unit neural recording via microelectrode arrays experiences deterioration in yield and quality over time, which is a major barrier to applications of this technology in long-term neuroscience research and clinical translation. There are many molecules and pathways involved in inflammation and neuronal death. We began our study by focusing on caspase-1, as caspase-1 is a key mediator of both inflammation and programmed cell death. Activation of caspase-1 is the earliest detectable event in neuronal apoptosis in vitro and in brains with ischemic, injury and neurodegenerative conditions. Furthermore, caspase-1 activates interleukin-1 ß (IL-1ß), a pro-inflammatory cytokine highly expressed in the tissue surrounding implanted electrodes, especially those that showed poor electrophysiological outcome. IL-1ß triggers inflammatory gliosis and exacerbates BBB breach; both are hypothesized causes of chronic recording failure. Therefore, we hypothesize that caspase-1 mediates the neuronal death and inflammation around neural implants and inhibiting caspase-1 may improve neuronal survival, reduce inflammation and lead to improved electrode performance. We have performed a preliminary study comparing the neural recording performance of microelectrode arrays implanted in caspase- 1 knockout (KO) vs. wild-type (WT) mice. The single unit yield and signal quality are significantly greater in the knockout animals over the 6 month time period, strongly supporting the critical role for caspase-1 in maintaining the quality of the electrode-tissue interface. However, closer examination of the recording over time revealed dynamic changes that cannot be interpreted with end-point histology. To better understand the mechanism(s) by which caspase-1-mediated pathways affect recording, we propose to use 2-photon live animal imaging to characterize the cellular and vascular responses to implanted neural probes in conjunction with neural recording and comprehensive tissue and biochemical analyses. Therapeutics targeting caspase-1 or the inflammation/cell death in general will be evaluated in an effort to improve the chronic neural interface. The drugs to be tested are caspase 1 specific inhibitor VX765, melatonin and minocycline. This proposal uses a multidisciplinary approach to uncover the molecular and cellular mechanism contributing to neural recording performance. The findings will increase our scientific understanding of neural implant pathology, and guide the development of therapeutic and/or biomaterial strategy for stable and reliable neural interface. Data and technology developed in this project may also contribute to the study of neuronal degeneration and inflammation in traumatic brain injury, stroke and neural degenerative diseases.