淫羊藿苷抑制小胶质细胞激活及调控NADPH oxidase通路在抗帕金森病中的作用机制研究

The mechanisms responsible for Parkinson's disease (PD) are not fully understood and current therapeutic treatments cannot halt PD progression. Microglia-mediated neuroinflammation and NADPH oxidase-generated reactive oxygen species (ROS) are thought to contribute to dopaminergic (DA) neuronal death. Thus, the inhibition of microglia-mediated neuroinflammation is becoming a promising therapeutic potential for PD. Icariin, a main active component of Epimedium, has been known to possess anti-oxidant, anti-inflammation and anti-aging properties. However, the neuroprotective effects of ICA on PD have not been elucidated. Here, based on our preliminary experiments, we found ICA produced neuroprotection against substantial nigral stereotaxic injection of lipopolysaccharide (LPS)-induced DA neurotoxicity. Moreover, ICA inhibited LPS-induced microglial activation and NADPH oxidase-generated ROS production, suggesting that the inhibition of microglial activation and NADPH oxidase-generated ROS production might be involved in ICA-mediated neuroprotection. Therefore, the present study further elucidated the neuroprotective effects of ICA on 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)- and LPS-induced 2 PD animal models. In addition, rat primary neuron-glia cocultures were performed to demonstrate the possible mechanisms underlying the role of ICA on microglia-mediated neuroinflammation. Taken together, this study extends our understanding of anti-inflammatory activities mediated by ICA and suggests that NADPH oxidase signaling pathways are important action sites for the treatment of PD.

帕金森病(PD)病因未明且临床缺乏有效治疗药物。小胶质细胞激活介导的神经炎症特别是小胶质细胞内NADPH oxidase(PHOX)调控的活性氧(ROS)释放被认为是多巴胺(DA)神经元死亡主要原因之一。因此，抑制小胶质细胞介导的神经炎症很可能成为治疗PD新策略。淫羊藿苷(ICA)是淫羊藿主要活性成分之一，具有抗炎、抗氧化、抗衰老等作用。但ICA防治PD的研究未见报道。课题组预实验发现：ICA保护大鼠中脑黑质注射LPS造成的DA神经元损伤，且抑制LPS 诱导的小胶质细胞激活并减少PHOX调控的ROS 释放，提示对小胶质细胞激活及PHOX的调控可能是ICA 神经保护重要机制之一。因此本项目拟通过MPTP和LPS诱导两种PD动物模型，进一步观察ICA治疗作用；并采用大鼠原代中脑神经元-胶质细胞共培养模型，深入探讨ICA 对小胶质细胞介导神经炎症及PHOX通路的调控机制，为ICA临床应用提供依据

帕金森病(PD)病因未明且临床缺乏有效治疗药物。小胶质细胞激活介导的神经炎症特别是小胶质细胞内NADPH oxidase (PHOX) 调控的活性氧 (ROS) 释放被认为是多巴胺 (DA) 神经元死亡主要原因之一。因此，抑制小胶质细胞介导的神经炎症很可能成为治疗PD新策略。淫羊藿苷(ICA)是淫羊藿主要活性成分之一，具有抗炎、抗氧化、抗衰老等作用。但ICA防治PD的研究未见报道。课题组预实验发现：ICA保护大鼠中脑黑质注射LPS造成的DA神经元损伤，且抑制LPS 诱导的小胶质细胞激活并减少PHOX调控的ROS 释放，提示对小胶质细胞激活及PHOX的调控可能是ICA 神经保护重要机制之一。因此本项目拟通过6-OHDA和LPS诱导的两种PD动物模型，观察ICA保护作用；并采用大鼠原代中脑神经元—胶质细胞共培养模型，深入探讨ICA 对小胶质细胞介导神经炎症及PHOX通路的调控机制。研究发现ICA对DA神经元变性损伤具有保护作用；并进一步明确ICA对小胶质细胞介导的神经炎症反应的调控作用机制，为ICA的临床应用提供基础药理学依据, 并为以 NADPH oxidase 信号转导通路为靶点防治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3篇，且IF均>5。申请人以第一完成人获得贵州省科技进步二等奖1项和申请发明专利2项。