Resveratrol Prevents Microelectrode Mediated Neurodegeneration

描述（由申请人提供）： 大脑皮层内电极记录的神经元电信号已被人类患者用于与计算机通信和控制机器人肢体。信号质量和有用信号可以被记录的时间长度是不一致的。社区的共识是，微电极的炎症反应至少部分地有助于电极的可靠性。 当炎症细胞识别外来生物制剂（即受损/浸润蛋白质和细胞）时，炎症开始。微电极植入后血清蛋白和血细胞侵入中枢神经系统。微电极植入会损伤细胞和组织。在微电极表面，促炎分子的积累引起神经元变性并增加血脑屏障的渗透性，使该过程自我延续。 我们已经表明，氧化应激是神经炎症反应的一个关键组成部分，微电极和氧化应激与神经元活力。与此同时，我们和其他人已经表明，对皮质内微电极的神经炎症反应与不稳定性直接相关， 神经记录。最重要的是，我们已经表明，白藜芦醇， 天然来源的抗氧化剂，暂时降低微电极介导的氧化应激，保持神经元活力，并促进稳定的神经记录。因此，我们的中心假设是，维持白藜芦醇的管理将提高长期的质量和稳定性的神经记录从皮质内微电极。 我们建议首先量化到什么程度，抗氧化剂，白藜芦醇，可以提高皮层内微电极神经记录的寿命和质量。接下来，为了最大限度地发挥临床影响，我们将研究两个关键问题：1）在记录的质量和稳定性已经下降之后，已经植入微电极的受试者是否可以证明神经记录的补救？2）患者需要持续服用白藜芦醇多长时间才能获得持久的功能效果？在整个拟定研究中，将对照稀释液处理的对照品，评价白藜芦醇处理的动物随时间推移获得的神经记录的寿命和质量（由活动通道数量及其信噪比定义）。此外，死后组织学将记录性能与氧化应激、神经保护和血脑屏障稳定性联系起来。 本研究旨在回答临床相关问题，并有可能在完成拟定研究后直接影响正在进行和未来的非人灵长类动物和临床试验。

DESCRIPTION (provided by applicant): Electrical signals recorded from neurons by intracortical electrodes have been used by human patients to communicate with computers and to control robotic limbs. The signal quality and the length of time that useful signals can be recorded are inconsistent. The consensus view of the community is that the inflammatory response to the microelectrode contributes, at least in part, to electrode reliability. Inflammation is initiated when inflammatory cells recognize foreign biologics (i.e. damaged/infiltrating proteins and cells). Serum proteins and blood-derived cells invade the central nervous system following microelectrode implantation. Cells and tissue are damaged from the trauma of microelectrode implantation. At the microelectrode surface, accumulation of pro-inflammatory molecules causes neuronal degeneration and increases the permeability of the blood-brain barrier, self- perpetuating the process. We have shown that oxidative stress is a key component of the neuroinflammatory response to microelectrodes and that oxidative stress correlates with neuron viability. In parallel, we and others have shown that the neuroinflammatory response to intracortical microelectrodes directly relates to the instability of neural recordings. Most importantly, we have shown that initial administration of resveratrol, a naturally-derived anti-oxidant, temporally reduces microelectrode-mediated oxidative stress, preserves neuron viability, and facilitates stable neural recordings. Therefore, our central hypothesis is that maintained administration of resveratrol will improve the long-term quality and stability of neural recordings obtained from intracortical microelectrodes. We propose to first quantify to what degree, the anti-oxidant, resveratrol, can improve the longevity and quality of intracortical microelectrode neural recordings. Next, to maximize clinical impact, we will examine two key questions: 1) Can subjects already implanted with microelectrodes demonstrate remediation of neural recordings after the quality and stability of the records has already declined? And 2) How long does a patient need to remain on resveratrol in order to obtain lasting functional outcomes? Throughout the proposed study, resveratrol-treated animals will be evaluated against diluent-treated controls for the longevity and quality of obtained neural recordings defined by the number of active channels and their signal-to-noise ratio, over time. Further, post-mortem histology will correlate recording performance to oxidative stress, neuroprotection and blood-brain barrier stability. This study is designed to answer clinically-relevant questions, and has the potential to directly impact ongoing and future non-human primate and clinical trials by the completion of the proposed study.