帕金森病(PD)治疗的首要任务是寻找具有多巴胺神经元保护活性的药物来干预病程。由于导致PD多巴胺神经元慢性变性的病因复杂，针对单一靶点药物难以凑效。利用中药多成分，多靶点作用特点研究神经保护中药干预PD病程具有重要的意义。前期我们证明南药益智仁在体内、外PD模型中具有良好的神经保护活性，但其活性物质基础及作用机理尚不明确；用益智仁提取物有效部位的LC-MS化学指纹图谱建立多元统计分析模型预测并活性导向分离到5个神经保护活性化合物。本项目拟研究这些化合物在体外对PD重要靶点MAO-B, NOS, Nrf2及NF-κB的调节作用；探讨活性化合物对Nrf2及NF-κB信号通路的调控机制；通过多元统计分析模型预测和在MPP+诱导的细胞损伤及MPTP诱导的斑马鱼PD模型上验证不同作用机理化合物间的协同效果。本项目将为益智仁研发成可干预多巴胺神慢性变性的防治PD的现代中药奠定理论基础。

Current therapies for Parkinson's disease (PD) relieve the symptoms; no one can halt or slow down the progress of degeneration of dopaminergic neurons. The conventional approach of using a single drug compound to act on a specific molecular target does not always effectively tackle this multi-etiology disease. Multiple drug therapy, such as traditional Chinese medicines with multiple-components and multiple targets, offers new hope in addressing complex pathological aspects by combining drug molecules with different mode of actions, acting on multiple malfunctioning targets and biological processes which cause the chronic and progressive degeneration of PD. Previously, we have demonstrated the neuroprotective effect of ethanolic extract of Frutus Alpinia oxyphylla (AOE) on iv vitro and in vivo models of PD. However, the active ingredients and mechanism of action are still unknown.5 active components have been predicted by multi-variant analysis using LC-MS chemical fringer printing of bioactive fractions of AOE and obtained by activity-guided isolation and identification. Based on these previous studies, this proposal aims to to investigate the effect of 5 active compounds on MAO-B, NOS, Nrf2 and NF-κB in vitro; to explore their mechanism of action on regulation of Nrf2 and NF-κB signal pathways; finally investigate the synergistic effect of active compounds with different model of action by multi-variants analysis prediction and experimental validation on MPP+ induced primary culture of SN neurons damage and MPTP-induced zebrafish PD model.This proposal will pave the way for development of Frutus Alpinia oxyphylla into modern Chinese medicine to prevent and treat PD by intervention of the degeneration progress of dopaminergic neurons.