Resveratrol Prevents Microelectrode Mediated Neurodegeneration

描述(由申请人提供)： 通过皮质内电极从神经元记录下来的电信号已经被人类患者用来与计算机通信和控制机器人肢体。信号质量和可记录有用信号的时间长度不一致。业界的共识是，对微电极的炎症反应至少在一定程度上有助于电极的可靠性。当炎症细胞识别外来生物物质(即受损/渗入的蛋白质和细胞)时，炎症就开始了。微电极植入后，血清蛋白和血源性细胞侵入中枢神经系统。微电极植入对细胞和组织造成损伤。在微电极表面，促炎分子的积累会导致神经元退化，并增加血脑屏障的通透性，使这一过程自我延续。我们已经证明，氧化应激是对微电极的神经炎性反应的关键组成部分，并且氧化应激与神经元活性相关。同时，我们和其他人已经证明，对皮质内微电极的神经炎性反应与这种不稳定性直接相关。 神经记录。最重要的是，我们已经证明了白藜芦醇的初始给药，一种 天然抗氧化剂，暂时减少微电极介导的氧化应激，保存神经元活性，并促进稳定的神经记录。因此，我们的中心假设是，维持白藜芦醇的使用将改善从皮质内微电极获得的神经记录的长期质量和稳定性。我们建议首先量化抗氧化剂白藜芦醇在多大程度上可以改善皮质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效果，我们将研究两个关键问题：1)已经植入微电极的受试者能否在记录的质量和稳定性已经下降后展示修复神经记录的能力？2)患者需要使用白藜芦醇多长时间才能获得持久的功能结果？在整个拟议的研究中，白藜芦醇处理的动物将与稀释剂处理的对照动物进行比较，以评估获得的神经记录的寿命和质量，这些记录由活动通道的数量及其信噪比随时间的推移而定义。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相关联。这项研究旨在回答与临床相关的问题，并有可能通过拟议研究的完成直接影响正在进行的和未来的非人类灵长类和临床试验。

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.