“异病同治”原则指导下的牛黄对脑梗死和淤胆型肝炎中内质网应激及PERK/eIF2α/ATF4通路的干预研究

Investigation of the shared mechanism of different diseases that can be treated by same medicine is an effective approach to find out the mechanism of Chinese medicine.Calculus bovis was reported to having a very strong efficacy on acute cerebral infarction and cholestatic hepatitis, while the mechanism is not very clear yet. T acute cerebral infarction and cholestatic hepatitis share the same characteristics of pathogenesis in TCM, called coma heat toxin entering Ying aspect. Modern studies demonstrate that cerebral and hepatic injury are closely related to endoplasmic reticulum stress (ERS), especially the PERK/eIF2α/ATF4 apoptosis pathway. Based on these information, we want to discuss whether the protection effect of calculus bovis on brain and liver is correlated to anti-endoplasmic reticulum stress and PERK/eIF2α/ATF4 apoptosis pathway? This proposal plans to study protection effect of calculus bovis and its two active component, namely taurine and hyodeoxycholic acid (HDCA),on brain and liver, to observe anti-ERS effect and regulating PERK/eIF2α/ATF4 apoptosis pathway effect both in vivo and in vitro,by establishing cerebral ischemic/reperfusion (I/R) and cholestatic hepatitis rats models, as well as primary neuron and hepatocyte ERS injured culture respectively. This study is designed to reveal the correlation between protection effect and anti-ERS effect of calculus bovis, partly elaborate its pharmacological efficacy ,explore the molecular mechanism of calculus bovis on PERK/eIF2α/ATF4 apoptosis pathway, to provide a new solution and approach to Chinese medicine mechanism research guided by principle of "same treatement to differernt diseases".

寻找"异病同治"的共性病机是研究中药作用机制的有效途径。据报道，牛黄对急性脑梗死和淤胆型肝炎均有显著疗效，但作用机制仍不完全清楚。两种疾病的共同中医病机为热毒入营，西医病机均与内质网应激（ERS）和PERK/eIF2α/ATF4凋亡通路密切相关。基于此，本课题以牛黄抗脑和肝损伤作用与ERS和PERK/eIF2α/ATF4凋亡通路的相关性为科学问题，通过脑缺血和淤胆型肝炎大鼠模型，以及原代神经元和肝细胞ERS损伤模型，观察牛黄及部分有效成分（猪去氧胆酸、牛磺酸）对脑缺血和胆汁淤积损伤的治疗药效，研究其抗ERS及抗凋亡作用，分析其对PERK/eIF2α/ATF4通路的调节机制。旨在揭示牛黄抗脑和肝损伤作用与ERS的相关性，阐释牛黄干预PERK/eIF2α/ATF4通路的具体分子机制，部分阐明牛黄解毒功效的现代药理机制，对牛黄研发和应用具有重要意义，且本研究还为探究中药作用机理提供了一种新思路。

寻找“异病同治”的共性病机是研究中药作用机制的有效途径。本课题建立了急性脑梗死和淤胆型肝炎两种大鼠模型，通过药理实验，分子生物学实验和细胞实验，揭示了两种疾病的共性机制为内质网应激（ERS）。牛黄中的有效成分能够通过调控PERK/eIF2α/ATF4凋亡通路改善两种病的病理状态，其中以牛磺熊去氧胆酸（TUDCA）效果最佳。本研究对牛黄的研发和应用具有重要意义，为探究重要作用机理提供了新思路。