锌稳态失衡对脑外伤后核因子-κB及继发性神经损伤的作用

The mechanisms contributing to the secondary neurologic lesions after traumatic brain injury (TBI) have not yet been well studied so far. After iron, zinc is the most abundant essential trace elements in the human body and has a wide distribution in the central nervous system. However, there are only a few researches investigating the pathophysiological role of zinc following the TBI. In our pilot studies, we found that zinc could activate NF-κB and induce neural damage following the TBI. However, the detailed mechanisms need to be further investigated. Combined with previous literature, we hypothesized that zinc-induced NF-κB activation is an important mechanism contributing to the secondary neurologic lesions after TBI. We demonstrate the role of zinc and NF-κB neurotoxicity after TBI at the cellular and systemic levels, using both multiple chemical compounds and lentiviral mediated gene silencing strategy. Our results provide some evidence based on "zinc dyshomeostasis→abnormal activation of NF-κB→neural damage", for deciphering the mechanism of the secondary neurologic lesions, and also provide new ideas to find new, more effective therapeutic drug targets following TBI.

创伤性脑损伤（traumatic brain injury, TBI）后继发性神经损害的发病机制目前尚未完全清楚。锌是体内含量仅次于铁的必须微量元素，尤其在神经系统分布广泛，但对锌在TBI中病理生理作用尚未见系统的研究报道。前期我们发现：锌能激活NF-κB和导致TBI后神经元损伤，但具体损伤机制不详。结合既往文献报道，我们提出：锌稳态失衡导致的NF-κB异常激活是TBI后继发性神经损伤的重要机制。本课题拟运用多种抑制剂、慢病毒转染、RNAi等技术配合EMSA、western blot等常见分子生物学检测手段，从分子、细胞、组织及临床标本等多方面论证锌、NF-κB在TBI后神经毒性的作用。本研究将从"锌稳态失衡→NF-κB异常激活→神经元损伤"这条新通路为揭示TBI后继发性神经损伤的发生机制奠定基础，为颅脑创伤找寻新的治疗靶点或药物提供新的思路。

创伤性脑损伤后继发性神经损害的发病机制目前尚未完全清楚。在本课题中我们提出假说并证实：锌稳态失衡导致的NF-κB异常激活是TBI后继发性神经损伤的重要机制。本研究包括三方面内容：.第一部分（临床实验）：在术中采取TBI患者挫伤脑组织（主要是皮层神经元）进行锌、炎症损伤、NF-κB、细胞凋亡等指标检测，我们发现人脑外伤后挫伤皮层神经元中有明显异常锌聚集、异常炎症反应、NF-κB的异常激活。. 第二部分（体内动物实验）：在大鼠创伤性脑损伤模型中，我们发现脑外伤后锌稳态的失衡可以异常激活NF-κB导致验证因子过度表达并导致神经元损伤，使用锌螯合剂后可明显抑制NF-κB激活、炎症因子的过表达，进而实现神经保护作用。.第三部分(体外细胞培养实验)：先在原代培养的神经元中，我们发现过量的锌可明显导致NF-κB激活、炎性因子的过表达，进而引起神经元损伤；使用锌螯合剂后可明显抑制NF-κB激活、炎症因子的过表达，进而实现神经保护作用。 .本研究提出的“锌稳态失衡→NF-κB异常激活→神经元损伤”这条新通路为揭示TBI后继发性神经损伤的发生机制奠定基础，为颅脑创伤找寻新的治疗靶点或药物提供新的思路。