植物大黄成分治疗脑外伤后认知功能障碍效应通路研究

At present, it is considered that inflammatory reaction is one of the causes of cognitive dysfunction after traumatic brain injury, but the specific mechanism is still unknown. Applicants previous research point out that rhubarb can inhibit the neuroinflammation reaction after traumatic brain injury and brain iron accumulation can cause cognitive impairment after traumatic brain injury. Hepcidin affects brain iron efflux has been confirmed through TLR4/MyD88 inflammatory signaling pathway.So we speculate that iron is the key point of cognitive dysfunction after traumatic brain injury in inflammatory mechanisms. Through a survey of the relationship between Rhubarb - nerve inflammation - iron - cognitive impairment, confirmed brain iron metabolism disorders mediated by inflammation may be the “common pathway”to produce cognitive disorders.In vitro research of this project to construct a human cell model, detection of iron efflux effect, in vitro biological function of rhubarb;according to the past research results of brain blast injury animal model, emodin blocking after traumatic brain injury and inflammatory signaling pathways, early molecular magnetic resonance imaging learn to assess changes in brain iron, late behavior evaluation of cognitive function, further shRNA iron regulating element control research, inflammation factor chip verification, to understand the relationship between cognitive dysfunction after inflammatory signaling,brain iron metabolism and traumatic brain injury, provide a new ideas to improve cognitive function after traumatic brain injury.

目前研究认为炎症反应是发生脑外伤后认知功能障碍原因之一，但具体机制仍不明了。申请者前期研究成果一方面发现大黄有效成分可抑制脑外伤后神经炎症反应改善认知功能障碍，另一方面明确了脑铁蓄积能加重认知功能损害，而脑外伤后TLR4/MyD88炎症信号通路上调铁调素水平导致脑铁蓄积现已得到证实，阐明了铁与神经炎症的密切关系。因此研究大黄有效成分与脑铁代谢之间的关系可能是揭示其治疗脑外伤后认知功能障碍机制的钥匙，通过“大黄-神经炎症-铁-认知障碍”关系研究，探寻炎症反应介导的脑铁代谢紊乱是否是产生认知障碍的效应通路。项目拟构建人源细胞模型，评估大黄有效成分对铁外排转运的影响，同时脑外伤动物模型干预，早期磁共振分子影像学检测脑铁含量，后期行为学认知功能评价，进一步shRNA干扰铁调素对照研究，炎症因子芯片检验，明确大黄有效成分与脑铁代谢及脑外伤后认知功能障碍的关系，为促进脑外伤患者认知功能康复提供新思路。

创伤性脑损伤是指由多种因素（坠落事件、汽车撞车事故、运动碰撞、火器袭击及爆炸等）导致的外部机械力作用于大脑的而产生的脑损伤。冲击波诱导的创伤性脑损伤是一种重要以及独特类型的TBI，在局部战争、反恐行动以及民用环境下都有发生。颅脑爆炸伤可导致不同程度的认知和行为损害，但其确切的脑组织病理生理机制尚不清楚以及理想的动物模型仍欠缺以及有效的治疗药物仍缺乏。本研究建立了一种新型基于压缩空气爆炸的单纯颅脑暴露、模拟真实世界的bTBI模型，发现大黄素、胸腺肽α1以及姜黄素治疗能改善颅脑爆炸伤所致神经和认知功能障碍，同时结合细胞模型并探讨了其可能的机制。结果发现：大黄素、胸腺肽α1以及姜黄素均能改善颅脑爆炸伤后认知功能以及炎症反应，本研究首次系统而全面地描述颅脑爆炸伤期间免疫细胞和血细胞时间变化的研究，首次发现胸腺肽α1改善了大鼠颅脑爆炸伤后认知功能障碍，这可能与抑制tau蛋白Thr205表位磷酸化、增加Treg细胞、减少炎症反应和脑水肿有关。首次发现姜黄素在颅脑爆炸伤后具有神经保护作用，可减少脑外伤后炎症因子和氧化应激的表达以及降低脑水肿含量，减弱血脑通透性被破坏的程度。