柚皮素调控NLRP3炎症小体对帕金森病的保护机制研究

The pathogenesis of Parkinson’s disease (PD) is not fully elucidated. Current clinical drugs cannot effectively treat PD. A number of studies demonstrate microglia-mediated neuroinflammation, particularly the activation of microglial NLRP3 inflammasome, are thought to contribute to dopamine (DA) neuronal death. Thus, the inhibition of microglial NLRP3 inflammasome activation is becoming a promising therapeutic potential for PD. Naringenin (NAR) has been confirmed to produce neuroprotection through multiple ways and multiple targets. However, the underlying neuroprotective mechanisms were not fully elucidated. Based on our preliminary experiments, we found NAR exerted neuroprotection against 6-hydroxydopamine (6-OHDA)-induced DA neuronal damage via the inhibition of microglia-elicited neuroinflammation and the subsequent activation of NLRP3 inflammasome, suggesting that the modulation of microglia-induced neuroinflammation and NLRP3 inflammasome-related signaling pathway might be responsible for NAR-mediated DA neuroprotection. Here, the present project aimed to further ascertain NAR-produced neuroprotection on PD. Then, primary rat midbrain neuron-glia co-culture was applied to investigate the effects of NAR on the activation of NLRP3 inflammasome and the underlying mechanisms. Finally, the NLRP3 gene knocknot mice were performed to evaluate the role of NLRP3 inflammasome signaling pathway in the effects of NAR on PD mouse model. Taken together, this study provides theoretical and experimental evidence for understanding NAR-conferred neuroprotection.

帕金森病(PD)发病机制未明且临床缺乏有效治疗药物。研究发现小胶质细胞介导的神经炎症，尤其是NLRP3炎症小体的活化在PD病理程中扮演重要角色，有望成为PD有效治疗靶标。柚皮素(NAR)是柚皮苷的苷元，研究发现NAR通过多途径、多靶点作用方式发挥神经保护作用, 但其确切保护机制尚不清楚。本课题组预实验发现：NAR保护大鼠中脑黑质注射6-OHDA造成的多巴胺能神经元损伤，同时改善小胶质细胞激活，并抑制小胶质细胞NLRP3炎症小体的活化；提示对小胶质细胞介导的神经炎症反应及NLRP3炎症小体相关通路的调控可能是NAR神经保护的重要机制之一。因此，本项目拟进一步明确NAR防治PD作用；其次通过大鼠中脑神经元—胶质细胞共培养，观察NAR对小胶质细胞NLRP3炎症小体活化的调控机制；并采用NLRP3基因敲除小鼠，观察NAR对PD小鼠模型的保护作用，以期为明确NAR的神经保护机制提供理论和实验依据。

帕金森病(PD)发病机制未明且临床缺乏有效治疗药物。研究发现小胶质细胞介导的神经炎症，尤其是NLRP3炎症小体的活化在PD病理程中扮演重要角色，有望成为PD有效治疗靶标。柚皮素(NAR)是柚皮苷的苷元，研究发现NAR通过多途径、多靶点作用方式发挥神经保护作用, 但其确切保护机制尚不清楚。本研究发现：NAR能够保护大鼠中脑黑质多巴胺能(DA)神经元损伤；同时改善小胶质细胞激活，并抑制小胶质细胞NLRP3炎症小体的活化；进一步研究发现将NLRP3基因沉默后，NAR抑制小胶质细胞介导的神经炎症反应减弱，且对DA神经元的保护作用消失。以上结果表明对小胶质细胞介导的神经炎症反应及NLRP3炎症小体相关通路的调控是NAR保护DA神经元的重要机制之一。因此，本研究为NAR的临床应用提供了基础药理学依据, 并为以 NLRP3炎症小题通路为靶点防治PD的药物研发提供新的研究思路。本项目研究成果目前共发表SCI收录论文4篇。申请人以第一完成人获得贵州省医学会医学科技奖一等奖1项和获批国家发明专利2项。