NF-κB介导室旁核内炎性反应促进颅脑损伤后交感兴奋的机制研究

Our clinical studies have shown that sympathetic hyperactivity after severe traumatic brain injury (TBI) is a serious complication, which is closely related to the prognosis and the pathogenesis is unknown. Studies have shown that sympathetic PVN inflamantory reaction is a pathological basis for the peripheral sympathetic hyperactivity. But it is not clear that inflamantory reaction in PVN whether increase sympathetic activity after TBI.Our preliminary test results support the hypothesis of inflamantory in PVN involving modulation of sympathetic hyperactivity. Therefore, this project aims to clarify the role and mechanism of inflamantory in PVN in sympathetic hyperactivity after TBI. A model of diffuse axonal injury in rats used, this project aim to explore by molecular biology and whole animal experoments:1) the role of inflamantory reaction in the sympathetic hyperactivity in PVN after TBI; 2)the role and mechnism of NF-κB activating inflamantory reaction in sympathetic hyperactivity after TBI. 3) the possible mechanism of inflamantory reaction in PVN increase sympatheic activity after TBI.This project's findings will provide the experimental basis to the inflamantory reaction hypothesis of sympathetic hyperactivity related to TBI, to help elucidate the pathogenesis of sympathetic hyperactivity, and provide new targets and methods for the sympathetic hyperactivity treatment after TBI.

课题组前期研究显示重型颅脑损伤（TBI）后交感兴奋与患者预后密切相关，目前发病机制不明。研究证实下丘脑室旁核（PVN）是多种病理情况下启动中枢交感兴奋的关键区域，但在TBI后交感兴奋的研究尚属空白。我们的预实验结果显示TBI后PVN内炎性因子水平显著升高，同时伴有小胶质细胞内NF-κB的激活，提示NF-κB介导的中枢炎性反应可能参与TBI后交感兴奋。本项目拟通过大鼠弥漫性轴索损伤模型，采用分子生物学、细胞培养和整体动物实验等法阐明：1）TBI后交感兴奋的变化规律和PVN内炎性反应；2）NF-κB介导PVN内炎性反应促进颅脑损伤后交感兴奋的机制；3)抑制PVN内炎性反应对TBI后交感兴奋的影响。通过以上研究将揭示NF-κB介导PVN内炎性反应促进TBI后交感兴奋的作用机制，有助于阐明TBI后交感兴奋的发病机制，为后续治疗研究提供新思路和新靶标。

NF-κB介导了室旁核内炎性反应促进颅脑损伤后交感兴奋的发生。本项目通过大鼠弥漫性轴索损伤模型，采用分子生物学、细胞培养和整体动物实验等方法对NF-κB介导PVN内炎性反应促进TBI后交感兴奋的作用机制进行了初步探究。.我们首先改进了弥漫性轴索损伤打击装置，建立了外伤后的大鼠交感神经兴奋模型。通过对模型的平均动脉压、心率、心率变异率及血浆去甲肾上腺素的测量确定了外伤后交感神经兴奋水平随时间变化规律，并进一步选取最佳观察点验证了室旁核内炎性因子的水平与交感兴奋水平变化存在相关性。通过给予抑制剂的方式，证明在颅脑损伤大鼠中TNF-α是调控交感兴奋的主要因子，并且NF-κB可以调控TNF-α表达进而调节交感神经兴奋程度。同时，应用弥漫性轴索损伤模型证明了外伤后室旁核内γ-氨基丁酸受体GABAA的表达存在上调，并通过立体定向室旁核内注射抑制剂的方法，阐明了室旁核内GABAA受体活性降低以及谷氨酸受体mGluR5 和NMDAR 活性上升可能是参与弥漫性轴索损伤急性期交感兴奋性升高的病理调控机制。该研究为探索外伤后交感神经兴奋的病理机制奠定了坚实的工作基础。