多巴胺减轻脊髓损伤后氧化应激损伤及其机制研究

Spinal cord injury (SCI) is a serious disease of the central nervous system with a high rate of disability. At present, there is a lack of effective intervention methods. Oxidative stress, which can cause nerve cell and tissue damage, is an important mechanism of secondary damage of SCI. Some studies have suggested that mitochondrial dysfunction increases the level of reactive oxygen species and NLRP3 inflammasome may induce mitochondrial dysfunction. Recent studies have demonstrated that dopamine is an endogenous inhibitor of NLRP3 inflammasome. And we found that the activation of dopamine D1 receptor can inhibit the activation of NLRP3 inflammasome in rats following SCI. Therefore, We propose the hypothesis that dopamine alleviates mitochondrial dysfunction ,oxidative stress injury and promotes neurological recovery following SCI. This project intends to establish cell and animal models of SCI, adopting the interventions of mitochondrial function regulator and blocking agent and NLRP3 gene silencing, to clear and define the function of mitochondrial dysfunction in oxidative stress injury after SCI, to investigate the effect and mechanism of dopamine on mitochondrial dysfunction and oxidative stress injury after SCI. The research can reveal the endogenous regulation mechanism of oxidative stress damage after SCI, and demonstrate the intervention effect of dopamine on SCI. Therefore, it is expected to provide a new way for the treatment of SCI and has a high clinical value.

脊髓损伤(SCI)是一种严重的中枢神经系统疾病，致残率高，目前缺乏有效的干预手段。氧化应激是SCI继发性损伤中的重要机制，可导致神经细胞和组织损伤。有研究提示线粒体功能障碍能够引起活性氧簇水平升高，而NLRP3炎性小体可能介导线粒体功能障碍。近期文献报道多巴胺是NLRP3炎性小体的内源性抑制剂，而我们发现激活多巴胺D1受体能够抑制大鼠SCI后NLRP3炎性小体活化，据此我们提出“多巴胺减轻SCI后线粒体功能障碍和氧化应激损伤，促进神经功能恢复”的假说。为此该项目拟建立SCI动物和细胞模型，采用线粒体功能调节剂、阻断剂和沉默NLRP3基因等干预措施，明确线粒体功能障碍在SCI后氧化应激损伤中的作用，探讨多巴胺减轻SCI后线粒体功能障碍和氧化应激损伤及其机制。该研究能够揭示SCI后氧化应激的内源性调控机制，明确多巴胺对SCI的干预效果，可望为SCI的治疗提供新途径，具有极高的临床实用价值。

脊髓损伤(Spinal cord injury, SCI)是一种严重的中枢神经系统疾病，致残率高，目前缺乏有效的干预手段。氧化应激和神经元死亡是SCI继发性损伤中的重要机制。我们的研究显示改善线粒体功能障碍能够减轻SCI后氧化应激。多巴胺能够抑制NLRP3炎性小体活化，改善线粒体功能障碍，减轻SCI后氧化应激，抑制细胞焦亡，减少神经元死亡，促进神经功能恢复。该研究揭示多巴胺减轻SCI后氧化应激的作用机制，明确多巴胺对SCI的干预效果。