复方丹参方有效成分对神经细胞氧化损伤的保护作用机制
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摘要
目的:复方丹参方被广泛用于治疗心血管疾病。近年来,实验及临床研究提示:复方丹参具有神经保护作用。因此本研究探讨复方丹参方的神经细胞保护作用机制,以期明确该复方成分与神经细胞靶分子的对应关系。
方法:本研究以氧化因子6-羟基多巴胺(6-OHDA)引起的神经细胞损伤和凋亡为模型,考察复方丹参方活性单体对6-OHDA引起的SH-SY5Y细胞凋亡及相关药理学指标的影响,分析其作用机制。通过培养人神经瘤母细胞(SH-SY5Y),观察了6-OHDA (100μmol/L,24小时)诱导损伤后SH-SY5Y细胞活力、胞内离子水平等的变化情况以及复方丹参方单体对氧化损伤的保护作用。
结果:通过帕金森病细胞模型进行具有神经保护活性单体成分的初步筛选,从30多种复方丹参方单体成分中筛选出有3种具有神经保护活性的单体,活性筛选结果表明人参皂苷Rg1、异龙脑(Iso)、Sal B保护作用明显,Rg1已有广泛深入的的神经保护作用机制研究,我们主要考察(±)异龙脑和丹酚酸B的神经保护作用及其作用机制。
Sal B显著的抑制6-OHDA导致的活性氧族物质的产生(reactive oxygen species, ROS) ,抑制6-OHDA导致的细胞内钙浓度升高。Heochest 33258染色和AnnexinⅤ-FITC/PI定量检测实验发现,Sal B抑制6-OHDA导致的凋亡,且呈现出剂量依赖关系。进一步对相关信号转导通路进行检测的结果表明:Sal B抑制6-OHDA导致的caspase-3活性升高,抑制cytochrome c从线粒体到胞质的移位。Sal B抑制6-OHDA导致的Bcl-2/Bax比率的降低。此外,Sal B抑制6-OHDA导致的细胞外信号调节蛋白激酶(extracellular signal-regulated kinase, p-ERK)活性的降低,抑制6-OHDA导致的蛋白激酶C (protein kinase C, PKC)活性的降低。异龙脑(Isoborneol, Iso)显著的抑制6-羟基多巴胺导致的ROS的产生,抑制6-OHDA导致的细胞内钙浓度升高。此外,Iso剂量依赖地抑制6-OHDA导致的凋亡。对相关信号转导通路深入研究的结果表明:Iso抑制6-OHDA导致的caspase-3活性升高,抑制cytochrome c从线粒体到胞质的移位。Iso抑制6-OHDA导致的Bcl-2/Bax比率的降低。此外,Iso抑制6-OHDA导致的c-Jun氨基末端激酶(c-Jun N-terminal kinase, p-JNK)的激活,Iso抑制6-OHDA导致的p-ERK活性的降低,抑制6-OHDA导致的PKC活性的降低。
综上所述,Sal B和Iso的神经保护作用可能与其抗氧化作用和调节细胞内钙平衡作用有关,其作用机制可能与其清除自由基和阻断凋亡信号通路有关。
结论:通过实验发现复方丹参方中活性单体可以通过抑制氧化应激反应(oxidative stress)和细胞凋亡发挥神经保护作用,为研究该方内组分神经保护作用的靶点提供了更为深入的资料,有助于揭示复方丹参方神经保护作用的物质基础和作用途径;在中药复方作用机制的阐释方面作出了有益的尝试。
Aim: The Chinese complex formula Fufangdanshen has been widely used to treat cardiovascular and nervous system diseases, and has been found to have beneficial effects on the nervous system including the effect of anti-Parkinson’s disease, while the molecular mechanism still needs further study. Parkinson's disease (PD) is the most common movement disorder. While the cause of PD is not known, data obtained from familial disease and from animal models of PD support a pathogenic process that is closely linked to mitochondrial dysfunction and oxidative stress. In this research, the neuro-protective effects of the active monomers in Fufangdanshen were observed and the related mechanisms were also studied.
Method: The PD in vitro model is built to quickly screen neuro-protective monomers from the Fufangdanshen formula in this experiment. Some researches focus on the molecular mechanisms of 6-OHDA induced damages and protective effects of salvianolic acid B and Isoborneol by means of cellular and molecular technologies.
The human neuroblastoma cell line SH-SY5Y was culutred, and several parameters were observed after 6-OHDA (100μmol/L,24hr) induced damage by pharmaceutical methods, including cell viability and the change of intracellular ion level, etc. The protective mechanism of salvianolic acid B and Isoborneol were studied.
Results: Experiments were carried to screen neuro-protective monoers from monomers in Fufangdanshen formula preliminary, and three of them show neuro-protective activies. Rg1, salvianolic acid B and Isoborneol showed protective effect dramatically. The neuro-protective mechanism of ginsenoside Rg1 we, so we focus on the protective mechanism of salvianolic acid B and Isoborneol.
Pretreatment of SHSY5Y cells with salvianolic acid B significantly reduced 6-hydroxydopamine-induced generation of reactive oxygen species, and prevented 6-hydroxydopamine-induced increases in intracellular calcium. Our Heochest 33258 staining and Annexin V-FITC/PI quantification data demonstrated that 6-hydroxydopamine-induced apoptosis was reversed by salvianolic acid B treatment. The related signal transduction pathway experiement showed that: Salvianolic acid B reduced the 6-hydroxydopamine-induced increase of caspase-3 activity, and reduced cytochrome C translocation into the cytosol from mitochondria. The 6-hydroxydopamine-induced decrease in the Bcl-x/Bax ratio was prevented by salvianolic acid B. Additionally, salvianolic acid B decreased the activation of extracellular signal-regulated kinase and induced the activation of 6-hydroxydopamine-suppressed protein kinase C.
Pretreatment of SH-SY5Y cells with isoborneol significantly reduced 6-OHDA-induced generation of reactive oxygen species (ROS) and 6-OHDA-induced increases in intracellular calcium. Furthermore, apoptosis induced by 6-OHDA was reversed by isoborneol treatment. Isoborneol protected against 6-OHDA-induced increases in caspase-3 activity and cytochrome C translocation into the cytosol from mitochondria. Isoborneol prevented 6-OHDA from decreasing the Bax/Bcl-2 ratio. We also observed that isoborneol decreased the activation of c-Jun Nterminal kinase and induced activation of protein kinase C (PKC) which had been suppressed by 6-OHDA.
In summary, Salvianolic acid B and isoborneol-mediated cytoprotection is due, at least in part, to inhibition of the oxidative stress and the regulation of intracellular calcium balance. Protective effects of salvianolic acid B and isoborneol are involved in its free radical scavenging actions and inhibitory effect on cell apoptosis.
Conclusion: Collectively, these results showed that the inhibition of oxidative stress and apoptosis may contribute to explain the the neuro-protective effect of monomers in Fufangdanshen formula. Furthermore, this research may explain the mechanism of traditional complex formula in the view of modern life science.
方法:本研究以氧化因子6-羟基多巴胺(6-OHDA)引起的神经细胞损伤和凋亡为模型,考察复方丹参方活性单体对6-OHDA引起的SH-SY5Y细胞凋亡及相关药理学指标的影响,分析其作用机制。通过培养人神经瘤母细胞(SH-SY5Y),观察了6-OHDA (100μmol/L,24小时)诱导损伤后SH-SY5Y细胞活力、胞内离子水平等的变化情况以及复方丹参方单体对氧化损伤的保护作用。
结果:通过帕金森病细胞模型进行具有神经保护活性单体成分的初步筛选,从30多种复方丹参方单体成分中筛选出有3种具有神经保护活性的单体,活性筛选结果表明人参皂苷Rg1、异龙脑(Iso)、Sal B保护作用明显,Rg1已有广泛深入的的神经保护作用机制研究,我们主要考察(±)异龙脑和丹酚酸B的神经保护作用及其作用机制。
Sal B显著的抑制6-OHDA导致的活性氧族物质的产生(reactive oxygen species, ROS) ,抑制6-OHDA导致的细胞内钙浓度升高。Heochest 33258染色和AnnexinⅤ-FITC/PI定量检测实验发现,Sal B抑制6-OHDA导致的凋亡,且呈现出剂量依赖关系。进一步对相关信号转导通路进行检测的结果表明:Sal B抑制6-OHDA导致的caspase-3活性升高,抑制cytochrome c从线粒体到胞质的移位。Sal B抑制6-OHDA导致的Bcl-2/Bax比率的降低。此外,Sal B抑制6-OHDA导致的细胞外信号调节蛋白激酶(extracellular signal-regulated kinase, p-ERK)活性的降低,抑制6-OHDA导致的蛋白激酶C (protein kinase C, PKC)活性的降低。异龙脑(Isoborneol, Iso)显著的抑制6-羟基多巴胺导致的ROS的产生,抑制6-OHDA导致的细胞内钙浓度升高。此外,Iso剂量依赖地抑制6-OHDA导致的凋亡。对相关信号转导通路深入研究的结果表明:Iso抑制6-OHDA导致的caspase-3活性升高,抑制cytochrome c从线粒体到胞质的移位。Iso抑制6-OHDA导致的Bcl-2/Bax比率的降低。此外,Iso抑制6-OHDA导致的c-Jun氨基末端激酶(c-Jun N-terminal kinase, p-JNK)的激活,Iso抑制6-OHDA导致的p-ERK活性的降低,抑制6-OHDA导致的PKC活性的降低。
综上所述,Sal B和Iso的神经保护作用可能与其抗氧化作用和调节细胞内钙平衡作用有关,其作用机制可能与其清除自由基和阻断凋亡信号通路有关。
结论:通过实验发现复方丹参方中活性单体可以通过抑制氧化应激反应(oxidative stress)和细胞凋亡发挥神经保护作用,为研究该方内组分神经保护作用的靶点提供了更为深入的资料,有助于揭示复方丹参方神经保护作用的物质基础和作用途径;在中药复方作用机制的阐释方面作出了有益的尝试。
Aim: The Chinese complex formula Fufangdanshen has been widely used to treat cardiovascular and nervous system diseases, and has been found to have beneficial effects on the nervous system including the effect of anti-Parkinson’s disease, while the molecular mechanism still needs further study. Parkinson's disease (PD) is the most common movement disorder. While the cause of PD is not known, data obtained from familial disease and from animal models of PD support a pathogenic process that is closely linked to mitochondrial dysfunction and oxidative stress. In this research, the neuro-protective effects of the active monomers in Fufangdanshen were observed and the related mechanisms were also studied.
Method: The PD in vitro model is built to quickly screen neuro-protective monomers from the Fufangdanshen formula in this experiment. Some researches focus on the molecular mechanisms of 6-OHDA induced damages and protective effects of salvianolic acid B and Isoborneol by means of cellular and molecular technologies.
The human neuroblastoma cell line SH-SY5Y was culutred, and several parameters were observed after 6-OHDA (100μmol/L,24hr) induced damage by pharmaceutical methods, including cell viability and the change of intracellular ion level, etc. The protective mechanism of salvianolic acid B and Isoborneol were studied.
Results: Experiments were carried to screen neuro-protective monoers from monomers in Fufangdanshen formula preliminary, and three of them show neuro-protective activies. Rg1, salvianolic acid B and Isoborneol showed protective effect dramatically. The neuro-protective mechanism of ginsenoside Rg1 we, so we focus on the protective mechanism of salvianolic acid B and Isoborneol.
Pretreatment of SHSY5Y cells with salvianolic acid B significantly reduced 6-hydroxydopamine-induced generation of reactive oxygen species, and prevented 6-hydroxydopamine-induced increases in intracellular calcium. Our Heochest 33258 staining and Annexin V-FITC/PI quantification data demonstrated that 6-hydroxydopamine-induced apoptosis was reversed by salvianolic acid B treatment. The related signal transduction pathway experiement showed that: Salvianolic acid B reduced the 6-hydroxydopamine-induced increase of caspase-3 activity, and reduced cytochrome C translocation into the cytosol from mitochondria. The 6-hydroxydopamine-induced decrease in the Bcl-x/Bax ratio was prevented by salvianolic acid B. Additionally, salvianolic acid B decreased the activation of extracellular signal-regulated kinase and induced the activation of 6-hydroxydopamine-suppressed protein kinase C.
Pretreatment of SH-SY5Y cells with isoborneol significantly reduced 6-OHDA-induced generation of reactive oxygen species (ROS) and 6-OHDA-induced increases in intracellular calcium. Furthermore, apoptosis induced by 6-OHDA was reversed by isoborneol treatment. Isoborneol protected against 6-OHDA-induced increases in caspase-3 activity and cytochrome C translocation into the cytosol from mitochondria. Isoborneol prevented 6-OHDA from decreasing the Bax/Bcl-2 ratio. We also observed that isoborneol decreased the activation of c-Jun Nterminal kinase and induced activation of protein kinase C (PKC) which had been suppressed by 6-OHDA.
In summary, Salvianolic acid B and isoborneol-mediated cytoprotection is due, at least in part, to inhibition of the oxidative stress and the regulation of intracellular calcium balance. Protective effects of salvianolic acid B and isoborneol are involved in its free radical scavenging actions and inhibitory effect on cell apoptosis.
Conclusion: Collectively, these results showed that the inhibition of oxidative stress and apoptosis may contribute to explain the the neuro-protective effect of monomers in Fufangdanshen formula. Furthermore, this research may explain the mechanism of traditional complex formula in the view of modern life science.
引文
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