苁蓉总苷和松果菊苷对体内外氧化应激阿尔茨海默病模型的作用及机理研究
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摘要
阿尔茨海默病(Alzheimer’s Disease，AD)是常发于老年人的一种痴呆性疾病，其主要病理特征为相对特异性的老年斑生成、神经元纤维缠结和神经元的丢失。研究表明，氧化应激与AD病理过程密切相关。H_2O_2或氧自由基是机体正常或异常代谢过程如β淀粉样蛋白聚集、多巴胺氧化和脑缺血再灌注的产物。生成的H_2O_2可以转变为高毒性的自由基攻击蛋白质、核酸和生物膜，导致线粒体损伤和钙超载等现象，诱发神经元走向凋亡。所以近年来已将氧化应激引起的神经退行性病变和细胞凋亡置于AD研究的中心位置，并将从天然产物中寻找具有抗氧化活性和抗自由基损伤的有效物质作为开发抗AD新药的重要途径。
苁蓉总苷是从管花肉苁蓉中提取得到的苯乙醇苷，苁蓉总苷胶囊由杏辉天力(杭州)药业有限公司生产，为SFDA批准的第一个以苯乙醇苷类化合物为主要成分的中药，对血管性痴呆的症状具有显著缓解作用。研究表明，苁蓉总苷具有抗氧化和神经细胞保护作用。松果菊苷是1950年第一个从狭叶紫锥菊中分离得到的苯乙醇苷类化合物，是苁蓉总苷的主要成分(含量＞25％)和主要的质量控制指标，也存在于其它植物中。研究表明，松果菊苷能保护肝损伤，对TNF-α诱导的SH-SY5Y细胞凋亡和6-羟基多巴胺引起的急性大鼠纹状体细胞损伤具有一定的保护作用。但有关其体外对氧化应激所致神经细胞损伤的保护作用研究很少。
本研究拟从氧化应激的角度分别利用整体动物模型和体外细胞模型研究苁蓉总苷及其主要成分松果菊苷对氧化应激损伤的保护作用和机理，为阐明苁蓉总苷的部分作用机制和开发利用松果菊苷提供依据。具体内容和结果如下：
1．苁蓉总苷可以明显改善D-半乳糖联合亚硝酸钠所致AD小鼠的学习记忆，提高小鼠或大鼠脑内Na~+-K~+ATPase、GSH-P_X和SOD的活性，降低NO的含量。
2．MTT法检测结果显示，松果菊苷可以明显提高H_2O_2损伤的PC12细胞存活率；流式细胞术和Hoechst 33342染色法形态观察结果表明，松果菊苷可以显著降低H_2O_2损伤PC12细胞的凋亡和坏死率，改善DNA片断化和核固缩，有抗PC12细胞凋亡作用；松果菊苷可以降低H_2O_2损伤PC12细胞LDH的渗漏。以上实验结果提示，松果菊苷对H_2O_2损伤的PC12细胞具有明显的保护作用。
3．在H_2O_2损伤PC12细胞模型上，检测了Na~+-K~+ATPase，GSH-P_X和Caspase-3三种酶活性的变化。研究发现，松果菊苷提高损伤细胞的Na~+-k~+ATPase，GSH-P_X的活性，但降低Caspase-3的活性。
4．Rhodamine 123和DCF-DA荧光染料结合流式细胞技术检测结果表明，松果菊苷可以显著升高损伤细胞的线粒体膜电位(MMP)，降低细胞内活性氧(ROS)水平。
5．Fluo-3和DAF荧光染料结合激光共聚焦检测结果显示，H_2O_2损伤的细胞内[Ca~(2+)]_i和NO显著升高，时程曲线上移。松果菊苷可以使损伤细胞内的[Ca~(2+)]_i和NO升高的速度和幅度都明显减缓，峰值降低。表明降低细胞内[Ca~(2+)]_i和NO与松果菊苷抑制PC12细胞凋亡的作用密切相关。
6．本实验用JC-1结合共聚焦技术进一步研究氧化损伤过程中PC12细胞MMP的变化和松果菊苷的干预作用。研究发现，用每个细胞的JC-1红色荧光强度和绿色荧光强度的比值(R)的变化值(R_0／R_t)最能体现MMP的变化，未见文献报道。200μM H_2O_2使细胞R_0/R_t变大，松果菊苷预处理使R_0／R_t变小，说明MMP升高。
7．Western blot检测结果发现，氧化损伤后PC12细胞Bcl-2低表达但Bax高表达，Bax／Bcl-2升高，松果菊苷处理有效抑制了H_2O_2的作用，使Bcl-2蛋白和Bax蛋白的表达回复到大约原来的水平，Bax／Bcl-2降低，说明抑制Bax表达和增强Bcl-2表达是松果菊苷抑制PC12细胞凋亡的重要机制之一。
8．RT-PCR半定量分析显示，PC12细胞在H_2O_2作用下，Bcl-2 mRNA表达显著降低，p53 mRNA、p65-2 mRNA和iNOS mRNA表达明显升高。松果菊苷可以拮抗H_2O_2的作用，逆转上述基因的表达，从而起到抗凋亡的作用。
本研究得出以下结论：1．苁蓉总苷可以4改善D-半乳糖联合亚硝酸钠AD模型小鼠的学习记忆，部分作用机理为提高脑内Na+~-K~+ATPase、GSH-P_X和SOD的活性，降低NO的含量。2．松果菊苷对H_2O_2损伤的PC12细胞损伤和凋亡具有明显的保护作用，升高Na~+-K~+ATPase，GSH-P_X的活性和MMP、降低细胞内ROS、Ca~(2+)以及NO水平、上调Bcl-2蛋白和mRNA表达但下调p53、p65和iNOS mRNA表达、降低Caspase-3的活性是其部分作用机制，说明松果菊苷通过抑制线粒体凋亡通路而发挥抗氧化应激的PC12细胞损伤作用。3．在增加其他药理实验和临床研究基础上，可以将苁蓉总苷用于其他老年性痴呆的预防和治疗；本文研究认为松果菊苷可能是治疗神经褪行性疾病如AD的有前景的候选化合物。
Alzheimer's Disease (AD) is one of the dementia diseases commonly happened insenior people,and pathologically characterized by the generation of senile plaquesand loss of neuron where the effects of oxidative stress are thought to play criticalroles.Researchs have shown that H_2O_2 and oxygen free radicals can be generated asbyproducts of normal and aberrant metabolic processes that utilize molecular oxygen,including amyloid aggregation,dopamine oxidation,and brain ischemia/reperfusion.Formed H_2O_2 can be converted into highly toxic hydroxyl radical to attack proteins,deoxynucleic acid,and lipid membrane,thereby leading to mitochondrialdysfunction,calcium imbalance,and apoptosis of neuronal cells.In recent years,researchers have focused more on effective substances for anti-oxidation andanti-free radicals from natural products for the treatment of AD.
In China,Cistanche tubulosa glycosides(CTG) isolated from the stems ofCistanche tubulosa (schrenk) Wight have been approved as a treatment for vasculardementia and produced by Sinphar TianLi Pharmaceutical Company (Hangzhou).This is the first government-approved drug containing phenylethanoid glycosides.Recent studies have shown that phenylethanoid glycosides are effective at scavengingfree radicals and protecting against glutamate-induced neurotoxicity.CTG alsoshowed antioxidant properties and neuroprotective function with echinacoside (ECH)as a quality control compound (content is more than 25%).ECH is the first compoundthat was defined as a phenylethanoid glycoside.It was first extracted from Echinaceaangustifolia in 1950 and exists in several other plants.ECH has recently beendemonstrated to protect hepatotoxicity and is a potent promoter of neuronal survivalinduced by TNF-αand MPTP.However,these studies provide limit information aboutthe protective effects of ECH on oxidative stress-induced injury in vitro.
This research is to study the protective effects of CTG and ECH on oxidativestress-induced injuries in vivo and in vitro,and disclose the related mechanisms forfurther developing CTG and ECH in the treatment of dementia diseases such as AD.
The results are shown as following:
1.CTG significantly ameliorated the learning and memory disorders induced byD-gal and sodium nitrite in mice with the increases of Na~+-K~+ATPase、GSH-Px andSOD activity and the decreases of the level of NO in mouse or rat brain.
2.Protective effects of ECH on H_2O_2-induced cytotoxicity in PC 12 cells weredemonstrated by the experiments as follows:(1) The cell viability was markedlyelevated and the leakage amount of LDH descended by ECH in H_2O_2-injured PC12cells;(2) Apoptosis and necrosis status was improved by ECH,which was confirmedby flow cytometry (FCM) and Hoechst 33342 staining.
3.The GSH-P_X and Na~+-K~+ ATPase activity were enhanced by ECH in H_2O_2-injuredPC12 cells,however,Caspase-3 activity was inhibited.
4.When PC 12 cells were exposed to H_2O_2,the intracellular ROS level wassignificantly increased with MMP decreasing.However,treatment with ECHeffectively reduced ROS generation and a significant increase of Rhodamine123fluorescence intensity was detected compared to H_2O_2 incubation alone.
5.Data obtained from LCSM suggested that the exposure to H_2O_2 irritation increased[Ca~(2+)]i and NO in PC12 cell rapidly.Treatment of ECH for 30 min prior to H_2O_2addition supressed the time course curve and caused a significant decrease of[Ca~(2+)]iand NO peak values.The study suggested that[Ca~(2+)]i and NO tightly involved in theprocess of apoptosis in H_2O_2-injured PC12 cells.
6.JC-1 and LCSM were used to confirm the effect of ECH on MMP in H_2O_2-injuredPC 12 cells as described above.R_0/R_t was used as the indicator of the change of MMP,in which R_0 is the ratio of red fluorescence intensity to green fluorescence intensity atthe beginning,and Rt is the ratio at one time after H_2O_2 irritation.The results showedthat ECH inhibited the increase of R_0/R_t in 20 min after H_2O_2 irritation.
7.We also measured the effect of ECH on H_2O_2-induced up-regulation of theBax/Bcl-2 ratio by Western blot.Bax protein expression in PC 12 cells wassignificantly increased,whereas the Bel-2 level was decreased.Pre-and co-treatmentwith ECH dramatically reduced the up-regulated Bax/Bcl ratio induced by H_2O_2.
8.To investigate whether there are any apoptotic gene expression changes involved in the apoptosis and the effects of ECH,the expression levels of Bcl-2,p53,p65 andiNOS mRNA were examined using RT-PCR.Decrease of Bcl-2 mRNA and increaseof p53,p65 and iNOS mRNA under the treatment of H_2O_2 were reversed by thetreatment of ECH to PC 12 cells.
Based on the above results,it is concluded that:(1) CTG significantlyameliorated the learning and memory disorders induced by oxidative stress,themechanisms may be related to the increase of Na~+-K~+ ATPase、GSH-Px and SODactivity as well as the decrease of the level of NO in brain.(2) the results suggestedthat ECH had markedly protective effects on H_2O_2-induced injury and apoptosis inPC12 cells by enhancing the GSH-P_X and Na~+-K~+ ATPase activity,inhibitingCaspase-3 activity and ROS,NO production,attenuating the MMP loss,preventingthe influx of Ca~(2+),up-regulating the expressions of the Bcl-2 protein and Bcl-2mRNA,and down-regulating the expressions of p53,p65 and iNOS mRNA.(3) CTGcan be used to prevent and treat senile dementia such as AD based on the experimentsand frether clinical tests.The data obtained from this study provided a sound basis toconfirm that ECH is a potential candidate for intervention in neurodegenerativediseases such as Alzheimer's and Parkinson's disease.
苁蓉总苷是从管花肉苁蓉中提取得到的苯乙醇苷，苁蓉总苷胶囊由杏辉天力(杭州)药业有限公司生产，为SFDA批准的第一个以苯乙醇苷类化合物为主要成分的中药，对血管性痴呆的症状具有显著缓解作用。研究表明，苁蓉总苷具有抗氧化和神经细胞保护作用。松果菊苷是1950年第一个从狭叶紫锥菊中分离得到的苯乙醇苷类化合物，是苁蓉总苷的主要成分(含量＞25％)和主要的质量控制指标，也存在于其它植物中。研究表明，松果菊苷能保护肝损伤，对TNF-α诱导的SH-SY5Y细胞凋亡和6-羟基多巴胺引起的急性大鼠纹状体细胞损伤具有一定的保护作用。但有关其体外对氧化应激所致神经细胞损伤的保护作用研究很少。
本研究拟从氧化应激的角度分别利用整体动物模型和体外细胞模型研究苁蓉总苷及其主要成分松果菊苷对氧化应激损伤的保护作用和机理，为阐明苁蓉总苷的部分作用机制和开发利用松果菊苷提供依据。具体内容和结果如下：
1．苁蓉总苷可以明显改善D-半乳糖联合亚硝酸钠所致AD小鼠的学习记忆，提高小鼠或大鼠脑内Na~+-K~+ATPase、GSH-P_X和SOD的活性，降低NO的含量。
2．MTT法检测结果显示，松果菊苷可以明显提高H_2O_2损伤的PC12细胞存活率；流式细胞术和Hoechst 33342染色法形态观察结果表明，松果菊苷可以显著降低H_2O_2损伤PC12细胞的凋亡和坏死率，改善DNA片断化和核固缩，有抗PC12细胞凋亡作用；松果菊苷可以降低H_2O_2损伤PC12细胞LDH的渗漏。以上实验结果提示，松果菊苷对H_2O_2损伤的PC12细胞具有明显的保护作用。
3．在H_2O_2损伤PC12细胞模型上，检测了Na~+-K~+ATPase，GSH-P_X和Caspase-3三种酶活性的变化。研究发现，松果菊苷提高损伤细胞的Na~+-k~+ATPase，GSH-P_X的活性，但降低Caspase-3的活性。
4．Rhodamine 123和DCF-DA荧光染料结合流式细胞技术检测结果表明，松果菊苷可以显著升高损伤细胞的线粒体膜电位(MMP)，降低细胞内活性氧(ROS)水平。
5．Fluo-3和DAF荧光染料结合激光共聚焦检测结果显示，H_2O_2损伤的细胞内[Ca~(2+)]_i和NO显著升高，时程曲线上移。松果菊苷可以使损伤细胞内的[Ca~(2+)]_i和NO升高的速度和幅度都明显减缓，峰值降低。表明降低细胞内[Ca~(2+)]_i和NO与松果菊苷抑制PC12细胞凋亡的作用密切相关。
6．本实验用JC-1结合共聚焦技术进一步研究氧化损伤过程中PC12细胞MMP的变化和松果菊苷的干预作用。研究发现，用每个细胞的JC-1红色荧光强度和绿色荧光强度的比值(R)的变化值(R_0／R_t)最能体现MMP的变化，未见文献报道。200μM H_2O_2使细胞R_0/R_t变大，松果菊苷预处理使R_0／R_t变小，说明MMP升高。
7．Western blot检测结果发现，氧化损伤后PC12细胞Bcl-2低表达但Bax高表达，Bax／Bcl-2升高，松果菊苷处理有效抑制了H_2O_2的作用，使Bcl-2蛋白和Bax蛋白的表达回复到大约原来的水平，Bax／Bcl-2降低，说明抑制Bax表达和增强Bcl-2表达是松果菊苷抑制PC12细胞凋亡的重要机制之一。
8．RT-PCR半定量分析显示，PC12细胞在H_2O_2作用下，Bcl-2 mRNA表达显著降低，p53 mRNA、p65-2 mRNA和iNOS mRNA表达明显升高。松果菊苷可以拮抗H_2O_2的作用，逆转上述基因的表达，从而起到抗凋亡的作用。
本研究得出以下结论：1．苁蓉总苷可以4改善D-半乳糖联合亚硝酸钠AD模型小鼠的学习记忆，部分作用机理为提高脑内Na+~-K~+ATPase、GSH-P_X和SOD的活性，降低NO的含量。2．松果菊苷对H_2O_2损伤的PC12细胞损伤和凋亡具有明显的保护作用，升高Na~+-K~+ATPase，GSH-P_X的活性和MMP、降低细胞内ROS、Ca~(2+)以及NO水平、上调Bcl-2蛋白和mRNA表达但下调p53、p65和iNOS mRNA表达、降低Caspase-3的活性是其部分作用机制，说明松果菊苷通过抑制线粒体凋亡通路而发挥抗氧化应激的PC12细胞损伤作用。3．在增加其他药理实验和临床研究基础上，可以将苁蓉总苷用于其他老年性痴呆的预防和治疗；本文研究认为松果菊苷可能是治疗神经褪行性疾病如AD的有前景的候选化合物。
Alzheimer's Disease (AD) is one of the dementia diseases commonly happened insenior people,and pathologically characterized by the generation of senile plaquesand loss of neuron where the effects of oxidative stress are thought to play criticalroles.Researchs have shown that H_2O_2 and oxygen free radicals can be generated asbyproducts of normal and aberrant metabolic processes that utilize molecular oxygen,including amyloid aggregation,dopamine oxidation,and brain ischemia/reperfusion.Formed H_2O_2 can be converted into highly toxic hydroxyl radical to attack proteins,deoxynucleic acid,and lipid membrane,thereby leading to mitochondrialdysfunction,calcium imbalance,and apoptosis of neuronal cells.In recent years,researchers have focused more on effective substances for anti-oxidation andanti-free radicals from natural products for the treatment of AD.
In China,Cistanche tubulosa glycosides(CTG) isolated from the stems ofCistanche tubulosa (schrenk) Wight have been approved as a treatment for vasculardementia and produced by Sinphar TianLi Pharmaceutical Company (Hangzhou).This is the first government-approved drug containing phenylethanoid glycosides.Recent studies have shown that phenylethanoid glycosides are effective at scavengingfree radicals and protecting against glutamate-induced neurotoxicity.CTG alsoshowed antioxidant properties and neuroprotective function with echinacoside (ECH)as a quality control compound (content is more than 25%).ECH is the first compoundthat was defined as a phenylethanoid glycoside.It was first extracted from Echinaceaangustifolia in 1950 and exists in several other plants.ECH has recently beendemonstrated to protect hepatotoxicity and is a potent promoter of neuronal survivalinduced by TNF-αand MPTP.However,these studies provide limit information aboutthe protective effects of ECH on oxidative stress-induced injury in vitro.
This research is to study the protective effects of CTG and ECH on oxidativestress-induced injuries in vivo and in vitro,and disclose the related mechanisms forfurther developing CTG and ECH in the treatment of dementia diseases such as AD.
The results are shown as following:
1.CTG significantly ameliorated the learning and memory disorders induced byD-gal and sodium nitrite in mice with the increases of Na~+-K~+ATPase、GSH-Px andSOD activity and the decreases of the level of NO in mouse or rat brain.
2.Protective effects of ECH on H_2O_2-induced cytotoxicity in PC 12 cells weredemonstrated by the experiments as follows:(1) The cell viability was markedlyelevated and the leakage amount of LDH descended by ECH in H_2O_2-injured PC12cells;(2) Apoptosis and necrosis status was improved by ECH,which was confirmedby flow cytometry (FCM) and Hoechst 33342 staining.
3.The GSH-P_X and Na~+-K~+ ATPase activity were enhanced by ECH in H_2O_2-injuredPC12 cells,however,Caspase-3 activity was inhibited.
4.When PC 12 cells were exposed to H_2O_2,the intracellular ROS level wassignificantly increased with MMP decreasing.However,treatment with ECHeffectively reduced ROS generation and a significant increase of Rhodamine123fluorescence intensity was detected compared to H_2O_2 incubation alone.
5.Data obtained from LCSM suggested that the exposure to H_2O_2 irritation increased[Ca~(2+)]i and NO in PC12 cell rapidly.Treatment of ECH for 30 min prior to H_2O_2addition supressed the time course curve and caused a significant decrease of[Ca~(2+)]iand NO peak values.The study suggested that[Ca~(2+)]i and NO tightly involved in theprocess of apoptosis in H_2O_2-injured PC12 cells.
6.JC-1 and LCSM were used to confirm the effect of ECH on MMP in H_2O_2-injuredPC 12 cells as described above.R_0/R_t was used as the indicator of the change of MMP,in which R_0 is the ratio of red fluorescence intensity to green fluorescence intensity atthe beginning,and Rt is the ratio at one time after H_2O_2 irritation.The results showedthat ECH inhibited the increase of R_0/R_t in 20 min after H_2O_2 irritation.
7.We also measured the effect of ECH on H_2O_2-induced up-regulation of theBax/Bcl-2 ratio by Western blot.Bax protein expression in PC 12 cells wassignificantly increased,whereas the Bel-2 level was decreased.Pre-and co-treatmentwith ECH dramatically reduced the up-regulated Bax/Bcl ratio induced by H_2O_2.
8.To investigate whether there are any apoptotic gene expression changes involved in the apoptosis and the effects of ECH,the expression levels of Bcl-2,p53,p65 andiNOS mRNA were examined using RT-PCR.Decrease of Bcl-2 mRNA and increaseof p53,p65 and iNOS mRNA under the treatment of H_2O_2 were reversed by thetreatment of ECH to PC 12 cells.
Based on the above results,it is concluded that:(1) CTG significantlyameliorated the learning and memory disorders induced by oxidative stress,themechanisms may be related to the increase of Na~+-K~+ ATPase、GSH-Px and SODactivity as well as the decrease of the level of NO in brain.(2) the results suggestedthat ECH had markedly protective effects on H_2O_2-induced injury and apoptosis inPC12 cells by enhancing the GSH-P_X and Na~+-K~+ ATPase activity,inhibitingCaspase-3 activity and ROS,NO production,attenuating the MMP loss,preventingthe influx of Ca~(2+),up-regulating the expressions of the Bcl-2 protein and Bcl-2mRNA,and down-regulating the expressions of p53,p65 and iNOS mRNA.(3) CTGcan be used to prevent and treat senile dementia such as AD based on the experimentsand frether clinical tests.The data obtained from this study provided a sound basis toconfirm that ECH is a potential candidate for intervention in neurodegenerativediseases such as Alzheimer's and Parkinson's disease.
引文
1黄克维，王鲁宁．神经病理学．北京：人民卫生出版社，1989：183-185．
2张振馨，ZahnerGE，RomanGC，等．中国北京、西安、上海和成都地区痴呆亚型患病率的研究．中国现代神经疾病杂志，2005；5(3)：156-7．
3 Ratnavalli E,Brayne C,Dawson K,et al.The prevalence of frontotenporal dementia.Neurology,2002;58(11):1615-1621.
4 Hebert LE,Beckett LA,Scherr PA,et al.Armual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050.Alzheimer Dis Assoc Disord,2001;15(4):169-173.
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