Department of Biomedical Engineering, Case Western Reserve University, 2071 Martin Luther King Jr Drive, Wickenden Bldg., Cleveland, OH 44106, USA.
Biomaterials. 2013 Sep;34(29):7001-15. doi: 10.1016/j.biomaterials.2013.05.035. Epub 2013 Jun 21.
The current study seeks to elucidate a biological mechanism which may mediate neuroinflammation, and decreases in both blood-brain barrier stability and neuron viability at the intracortical microelectrode-tissue interface. Here, we have focused on the role of pro-inflammatory reactive oxygen species. Specifically, adult rats implanted within intracortical microelectrodes were systemically administered the anti-oxidant, resveratrol, both the day before and the day of surgery. Animals were sacrificed at two or four weeks post-implantation for histological analysis of the neuroinflammatory and neurodegenerative responses to the microelectrode. At two weeks post-implantation, we found animals treated with resveratrol demonstrated suppression of reactive oxygen species accumulation and blood-brain barrier instability, accompanied with increased density of neurons at the intracortical microelectrode-tissue interface. Four weeks post-implantation, animals treated with resveratrol exhibited indistinguishable levels of markers for reactive oxygen species and neuronal nuclei density in comparison to untreated control animals. However, of the neurons that remained, resveratrol treated animals were seen to display reductions in the density of degenerative neurons compared to control animals at both two and four weeks post-implantation. Initial mechanistic evaluation suggested the roles of both anti-oxidative enzymes and toll-like receptor 4 expression in facilitating microglia activation and the propagation of neurodegenerative inflammatory pathways. Collectively, our data suggests that short-term attenuation of reactive oxygen species accumulation and blood-brain barrier instability can result in prolonged improvements in neuronal viability around implanted intracortical microelectrodes, while also identifying potential therapeutic targets to reduce chronic intracortical microelectrode-mediated neurodegeneration.
当前的研究旨在阐明一种可能介导神经炎症的生物学机制，以及在皮质内微电极-组织界面处血脑屏障稳定性和神经元活力的降低。在这里，我们关注的是促炎活性氧物质的作用。具体来说，将成年大鼠植入皮质内微电极中，并在手术前一天和手术当天全身给予抗氧化剂白藜芦醇。在植入后两到四周，对动物进行组织学分析，以研究微电极对神经炎症和神经退行性反应的影响。在植入后两周，我们发现用白藜芦醇处理的动物表现出活性氧物质积累和血脑屏障不稳定的抑制作用，同时皮质内微电极-组织界面处神经元密度增加。在植入后四周，与未处理的对照动物相比，用白藜芦醇处理的动物表现出活性氧物质和神经元核密度标志物的水平无明显差异。然而，与对照动物相比，在植入后两周和四周，用白藜芦醇处理的动物的退行性神经元密度降低。初步的机制评估表明，抗氧化酶和 Toll 样受体 4 表达的作用在促进小胶质细胞激活和神经退行性炎症途径的传播中发挥作用。总的来说，我们的数据表明，短期抑制活性氧物质积累和血脑屏障不稳定性可以导致植入皮质内微电极周围神经元活力的长期改善，同时也确定了减少慢性皮质内微电极介导的神经退行性变的潜在治疗靶点。
