中药肝豆汤治疗Wilson病疗效机制的研究进展

Research Progress of Therapeutic Mechanism of Gandou Decoction in Treatment of Wilson's Disease

Wilson病(WD)是一种以铜代谢障碍为生化特征的可治性神经遗传病,目前以青霉胺(PCA)为代表的金属络合剂驱铜治疗等治疗方法存在一定的局限性,使其治疗范围和效果受到限制,基因治疗尚处于实验室研究阶段,走向临床尚需时日。笔者等在现代医学对WD认识的基础上,根据对WD中医病机、证候学、中药方剂治疗学等方面的研究结果,创用中药组方肝豆汤治疗WD患者,获得了良好的临床疗效。基于此,笔者等在多个国家自然科学基金项目的资助下,从铜代谢的分子通路,Wnt/β-catenin通路和丝裂原激活的蛋白激酶(MAPK)通路等调控肝损伤的细胞信号通路,细胞外信号调节激酶(ERK)通路和肝激酶B1(LKB1)/腺苷酸活化蛋白激酶(AMPK)通路等调控神经元损伤的细胞信号通路等角度对肝豆汤治疗WD的疗效机制进行了系列研究,结果发现中药组方肝豆汤能多层次、多靶点调控铜代谢障碍所致的WD肝细胞和神经元细胞的调亡、自噬等细胞程序性死亡过程,并通过TX小鼠等WD的动物模型验证了上述实验结果,从而证明了肝豆汤组方的合理性、配伍的必要性和用药的准确性,并为肝豆汤组分的进一步优化提供了依据。文章最后对肝豆汤治疗WD疗效机制的未来研究方向提出了一些设想和可行性建议。

Wilson disease(WD)is a treatable neurological inherited disorder characterized by copper metabolism impairment.Metal chelating drugs,such as penicillamine,have been used to treat WD for decades,is exposuring its limitations of effect and utilize sphere.Genetic therapy was considered as the most potential way of curing WD,is still can only be achieved in the laboratory,which have massive problems to solve before its clinical utilization.Based on this,we started to research the curative mechanism of traditional Chinese medicine(TCM)donated by national natural science fund project funding,found that TCM formula Gandou decoction regulate the metabolic disorders caused by liver cells and neurons apoptosis,autophagy,such as programmed cell death,from the molecular pathways of copper metabolism,Wnt/β-catenin pathway and mitogen-activated protein kmase(MAPK)pathways regulating liver damage such as cell signaling pathways,extracellular signal-regulated kinase(ERK)pathway and liver kinase B1(LKB1)/adenosine monophosphate activated protein kinase(AMPK)pathway and the cell signaling pathway of neuronal damage.The above experimental results were verified by TX mice,a reliable WD animal models.This paper aimed to systematically review the research of GDD therapeutic mechanisms from the sight of programmed cell death,including aptosis and autophagy,and provided theoretical for formula optimization.In addition,we elaborated some assumptions and feasible advice for the further research of GDD therapeutic mechanism.