熊胆粉及其活性成分治疗神经系统疾病作用机制研究进展

Research progress on the mechanism of bear bile powder and its active ingredients in the treatment of nervous system diseases

熊胆粉活性成分熊去氧胆酸(ursodesxycholic acid, UDCA)、牛磺熊去氧胆酸(tauroursodeoxycholic acid, TUDCA)在不同的神经系统疾病动物模型中具有神经保护作用。其中UDCA、TUDCA可通过抑制丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路中细胞外调节蛋白激酶(extracellular regulated protein kinase, ERK)、c-Jun氨基末端激酶(c-Jun N-terminal kinasa, JNK)、p38 MAPK的磷酸化发挥抗神经炎症的作用;UDCA通过激活单磷酸腺苷活化蛋白激酶(AMP-activated protein kinase, AMPK)/雷帕霉素靶蛋白(mechanistic target of rapamycin, mTOR)和抑癌基因诱导的假定激酶蛋白1(PTEN induced putative kinase 1,PINK1)/RBR E3泛素蛋白连接酶(RBR E3 ubiquitin-protein ligase, Parkin)信号通路,抑制小鼠帕金森病(parkinson’s disease, PD)中神经细胞凋亡,增加线粒体自噬起到改善线粒体功能障碍和神经保护的作用。熊胆粉、TUDCA通过上调G蛋白偶联受体(G protein-coupled bile acid receptor 5,TGR5)的表达抑制蛋白激酶B(protein kinase B, Akt)/核因子-κB(nuclear factor-κB,NF-κB)信号通路的激活及调控巨噬细胞的分化,减轻神经炎症反应,保护神经细胞;TUDCA下调蛋白激酶R样内质网激酶(protrin kinase R-like ER kinase, PERK)/PERK-真核细胞起始因子2α(eukaryotic initiation factor 2α,eIF2α)/转录激活因子4(activating transcription factor 4,ATF4)/C/EBP同源蛋白(C/EBP-homologous protein, CHOP)信号通路的表达,上调CIBZ基因的表达,激活核因子E2相关因子2(nuclear factor-erythroid 2 related factor 2,Nrf2)/NADPH醌氧化还原酶1(NADPH quinone oxidoreductase 1,NQO1)、TGR5/去乙酰化酶3(recombinant sirtuin 3)等信号通路,抑制内质网应激、氧化应激所引起的神经细胞调亡,TUDCA通过调节细胞自噬和能量代谢抑制细胞凋亡发挥神经保护作用。现将近年来对熊胆粉、UDCA、TUDCA治疗神经系统病作用机制进行综述,为熊胆粉及其活性成分的临床运用提供参考。

Ursodesxycholic acid(UDCA)and tauroursodeoxycholic acid(TUDCA),the active components of bear bile powder,have neuroprotective effects in different animal models of nervous system diseases.Among them,UDCA and TUDCA can play anti-neuroinflammatory role by inhibiting the phosphorylation of extracellular regulated protein kinase(ERK),c-Jun N-terminal kinasa(JNK)and p38 MAPK in mitogen-activated protein kinase(MAPK)signaling pathway.By activating AMP-activated protein kinase(AMPK)/mechanistic target of rapamycin(mTOR)and PINK1/Parkin signaling pathways,UDCA inhibits neuronal apoptosis in Parkinson's disease(PD)model mice and increases mitophagy to play a improve mitochondrial dysfunction and neuroprotective role.By up-regulating the expression of G protein-coupled bile acid receptor 5(TGR5),bear bile powder and TUDCA inhibit the activation of serine threonine kinase(Akt)/nuclear factor-κB(NF-κB)signaling pathway and regulate the differentiation of macrophages,reduce neuroinflammation and protect nerve cells.TUDCA down-regulated the expression of protein kinase R-like ER kinase(PERK)/PERK-eukaryotic initiation factor 2α(eIF2α)/activating transcription factor 4(ATF4)/C/EBP-homologous protein(CHOP)signaling pathway.Up-regulation of CIBZ gene expression,activation of nuclear factor-erythroid 2 related factor 2(Nrf2)/NADPH quinone oxidoreductase 1(NQO1),TGR5/recombinant sirtuin 3 and other signaling pathways,inhibit neuronal apoptosis caused by endoplasmic reticulum stress and oxidative stress.TUDCA inhibits apoptosis by regulating autophagy and energy metabolism play a neuroprotective role.This article reviews the mechanism of the active components of bear bile powder in the treatment of nervous system diseases in recent years,and provides a reference for the clinical application of bear bile powder and its active components.