中文摘要
以中医药理论为指导,现代科学技术为支撑,针对马钱子致神经毒性作用和白芍配伍减毒效应核心问题,从药物对机体影响和机体对药物处置两方面,以整体动物-靶器官-细胞关联角度,集成创新性地提出了动态生物网络体系研究思路。.首先,以细胞毒理效应和体内模型为指导,筛选毒性部位(成分);其次,对致神经毒性作用马钱子和回调药白芍的化学成分及血-各脑区移行成分进行动态、定量指纹图谱分析,阐明毒性(药效)物质基础;进而,对中毒大鼠血、脑内源性物质变化追踪,确认敏感、特异性生物标记物,推断代谢通路和脑部靶向性;进一步,在细胞和分子水平上对马钱子(白芍)调控细胞网络分子机理研究,追踪细胞内特定蛋白、细胞因子表达水平变化,揭示马钱子(白芍)神经毒性(干预作用)相关通路,探讨神经损伤可能机制。最终,从“物质基础-毒性效应-损伤机理角度,达到物质组分清晰、作用靶点明确、机制清楚目标,为安全用药和解毒药资源开发提供科学依据
英文摘要
Our study is conducted under the guidance of Chinese medical theory, modern analytical science and technology, focusing on the core issues of the neurotoxicity induced by Semen strychni and the protective effects of Radix Paeoniae Alba. The toxic (effect) components and mechanism are to be investigated integratively and innovatively based on an idea of dynamic bio-network system in the perspective of the interaction of herb and body..With the direction of Cell-based toxic screening and pharmacological models in vivo, the toxic part (components) of Semen strychni extract is going to be screened out. Then the quantification of dynamic profiles of the extract of Semen strychni and Radix Paeoniae Alba in vitro and in vivo (blood and different brain regions) is to be carried out to clarify the potential toxic (effect) substances. Furthermore, a set of biomarkers which are related to neurotoxicity and used for early diagnosis and clinical prevention, will be obtained from the quantification of sensitive endogenous substances in the blood and brain. These results will be helpful to identify the metabolic pathways and target regions in the brain involved in neurotoxicity. .According to the research on the cellular and molecular mechanisms mediated by Semen strychni (Radix Paeoniae Alba), the changes of the expression levels of specific proteins and cytokines in PC12 cells are traced at the molecular level in order to elucidate metabolic pathways and investigate the neurotoxicity(intervention) mechanism induced by Semen strychni (Radix Paeoniae Alba). Ultimately, the goals will be obtained to recognize its toxic (effect) components, identify the brain target regions and demonstrate its toxic (effect) mechanism from an integral view of material basis, toxic effects and damage mechanism. Our findings are promising to provide beneficial information for further understanding and better using of Semen strychni and might be helpful to develop new antidotal herb in clinical.
