NLRP3炎症小体在糖尿病周围神经病变中的作用机制及中药筋脉通干预研究

It is well established that oxidative stress and inflammation are critical factors in the pathogenesis of diabetic peripheral neuropathy (DPN). Recent studies have focused on the effect of nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing (NLRP) 3 inflammasome. NLRP 3 inflammasome is induced and activated by oxidative stress, and regulates the maturation and secretion of inflammatory cytokines IL-1βand IL-18 via its activation of caspase-1, causing the inflammation in diabetes and its chronic complications. However, the role of NLRP 3 in the pathogenesis of DPN has not been reported. NLRP 3 inflammasome is expressed in the glial cells of the central nervous system, and has close correlation with neuroinflammation. Schwann cells are important glial cells in the peripheral nervous system, indicating its possible role in DPN. Previous studies have shown the effectiveness of Jinmaitong Capsule in treating DPN, improvement of neural conduction velocity in DPN mice, and anti-oxidation and anti-inflammatory effect. In the present study, we set to investigate the effect of Jinmaitong Capsule on the activation of NLRP3 inflammasome in DPN, and its relationship with upstream oxidative stress as well as downstream inflammatory reactions by using DPN mouse model and high glucose Schwann cell model. The goal of this study is to provide theoretical bases and experimental evidence for the clinical application of Jinmaitong Capsule.

目前公认氧化应激和炎症反应是糖尿病周围神经病变（DPN）的重要发病机制，近期研究集中于核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎症小体的作用，它可由氧化应激诱导激活，并通过活化半胱天冬酶-1（caspase-1）调控IL-1β、IL-18等炎症因子的成熟和分泌，引发糖尿病及慢性并发症中的炎症，但在DPN中的作用尚未见报道。NLRP3炎症小体在中枢神经系统胶质细胞中表达，与神经炎症反应密切相关，雪旺细胞是周围神经系统重要的胶质细胞，故其可能在DPN发病中起重要作用。既往研究证实中药筋脉通治疗DPN临床疗效良好，能够改善DPN大鼠的神经传导速度，具有较好的抗氧化和抗炎作用。本课题拟采用DPN 大鼠模型、高糖培养雪旺细胞模型，利用分子生物学技术探讨筋脉通对DPN时周围神经NLRP3炎症小体激活的影响，及其与上游氧化应激和下游炎症反应的关系，进一步为筋脉通的临床应用提供理论基础和实验依据。

糖尿病周围神经病变是糖尿病最常见的慢性并发症之一，严重影响患者的生活质量，其发病机制复杂，尚未完全阐明，目前缺乏有效治疗药物。中药复方具有多靶点、多通路调节的优势，筋脉通具有补肾活血、温通筋脉的功效，临床治疗糖尿病周围神经病变疗效确切。本项目在前期研究证实筋脉通有抗氧化应激和抗炎作用的基础上，进一步阐明筋脉通及其主要活性成分槲皮素能够下调链脲佐菌素诱导的糖尿病大鼠坐骨神经和高糖刺激的RSC96雪旺细胞TXNIP/NLRP3炎症小体通路，抑制Caspase-1活化，减少IL-1β、IL-18等炎症因子分泌，从而改善糖尿病大鼠周围神经痛及坐骨神经损伤，其作用与拮抗NLRP3炎症小体有关。研究结果为糖尿病周围神经病变的机制研究开拓新的思路，为药物筛选提供新的靶标，为筋脉通的临床应用提供证据，为中药新药转化和推广奠定基础。