玉郎伞多糖抗痴呆作用及机制的研究
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摘要
阿尔茨海默症(Alzheimer's disease, AD)是老年痴呆症的首要病因,是一多发在老年,以近期记忆障碍为主要临床症状,以老年斑(SP)、神经元纤维缠结(NFT)和神经元丢失为主要病理改变的进行性神经变性疾病,严重影响患者的认知功能、记忆功能、语言功能、视空间功能、社会生活能力、个人生活能力和情感人格等,其病因和发病机制尚不清楚。目前受到广泛认同的病因和机制主要有以下几种学说：神经递质缺陷；钙稳态失调；自由基损伤；基因突变；能量代谢障碍；神经细胞凋亡；兴奋性递质毒性；淀粉样蛋白(Ap)沉积等。玉郎伞(Millettia pulchra Kurz var laxior(Dunn) Z.Wei, YLS)是广西壮族习用药材,有补气、补血、提高免疫力、抗衰老、抗应激等作用,可强身健体、消除疲劳,主要用于老年健忘、小儿智力低下等疾病的治疗,亦用于体弱多病及病后、产后虚弱等的滋补。本研究从玉郎伞提取多糖成分,并对玉郎伞多糖[Millettia pulchra Kurz var laxior(Dunn) Z. Wei polysaccharides, YLSP]抗痴呆作用及机制进行了研究。
1、正交法优化YLSP提取工艺及含量测定方法的研究
葡萄糖的检测浓度在15.12-65.52μg·mL-1范围内与吸光度呈现良好的线性关系,结果精密度高,平均加样回收率为98.25%,RSD=1.72%；通过提取条件的正交试验发现,浸泡3小时、加10倍量水、提取3次,每次3小时条件下YLSP得率最高。因此,通过优化提取条件,能够提高YLSP的得率和纯度。苯酚-硫酸法准确度高、稳定性好,可作为YLSP的含量测定方法。
2、YLSP对AP25-35诱导PC12细胞损伤的保护作用
采用AP25-35诱导PC12细胞损伤作为AD细胞模型,通过MTT比色法测定分析细胞存活率；倒置相差显微镜、透射电镜观察细胞形态改变,测定细胞突起率、突起平均长度；分光光度法检测PC12细胞细胞培养液和(或)细胞内的SOD、GSH-Px和NOS活性,GSH、MDA、NO和LDH的含量；流式细胞仪测定PC12细胞内ROS、钙离子的含量及线粒体膜电位(MMP)。结果显示：Aβ25-35对PC12细胞具有明显的损伤作用,增加细胞死亡率,减少细胞突起率,缩短细胞突起长度,镜下表现出明显的凋亡损伤形态,细胞培养液和(或)细胞内的NOS活性及NO、MDA、ROS、 LDH和钙离子含量明显升高,而SOD、GSH-Px活性及GSH的含量明显降低,MMP也明显降低。YLSP能在一定程度抑制Aβ25-35对PC12细胞的损伤作用：降低细胞死亡率,增加细胞突起率,延长细胞突起长度,镜下凋亡损伤形态显著改变,细胞膜上微绒毛增多,空泡减少,明显降低PC12细胞细胞培养液和(或)细胞内的NOS活性及NO-、MDA、ROS、LDH和钙离子含量,明显提高PC12细胞细胞培养液中及细胞内SOD、GSH-Px活性及GSH的含量,明显提高MMP水平。提示YLSP可能是通过减少脂质过氧化产物的形成、增加抗氧化酶的抗氧化活性,增强细胞总的抗氧化活力而发挥抗痴呆作用。
3、YLSP对Aβ25-35诱导PC12细胞凋亡的保护作用
采用流式细胞仪、DAPI染色方法观察测定PC12细胞凋亡率,Real-time PCR测定PC12细胞凋亡相关基因p53、Bcl-2、Bax及Caspase-3mRNA表达。结果显示：Aβ25-35能明显增加PC12细胞的凋亡,促凋亡基因p53、Bax、 Caspase-3的mRNA表达含量明显升高,抑凋亡基因Bcl-2基因的mRNA表达含量明显降低。YLSP能显著减少Aβ25-35引起的PC12细胞凋亡,降低细胞凋亡率,降低促凋亡基因p53、Bax、Caspase-3的mRNA表达含量,增加抑凋亡基因Bcl-2mRNA表达含量。提示YLSP可以拮抗Aβ25-35引起的PC12细胞凋亡,逆转上述基因的表达,从而起到抗凋亡的作用。
4、YLS1'对SAMP8小鼠额叶、海马神经元Caspase-3表达及活性、Tau蛋白磷酸化的影响
采用快速老化小白鼠(senescence accelerated mouse prone8, SAMP8)作为AD动物模型,通过免疫组化的方法观察YLSP对SAMP8小鼠额叶、海马的病理变化,神经元细胞Caspase-3的表达及tau蛋白磷酸化水平的影响。结果显示：SAMP8小鼠额叶、海马神经细胞凋亡明显,Caspase-3阳性细胞数、Caspase-3活性和Tau (pSer202)阳性细胞数均明显高于SAMR1对照小鼠。YLSP能显著减少SAMP8小鼠额叶、海马神经细胞Caspase-3和Tau (pSer202)阳性细胞数,降低Caspase-3活性,提示YLSP能通过抑制凋亡,拮抗Tau (Ser202)的异常磷酸化而发挥抗痴呆的作用。
综上所述,YLSP可能是通过清除自由基、对抗氧化应激反应,减少Ca2+内流及LDH释放、提高线粒体膜电位水平,抑制p53、Bax、Caspase-3基因mRNA表达,促进Bcl-2基因的mRNA表达,拮抗Tau (Ser202)的异常磷酸化等机制而达到抗痴呆作用。本文研究认为YLSP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 is one kind of disease characterized by recent memory handicap, senile plaque(SP), neurofibrillary tangle(NFT), and neuron loss in pathology and gradually neuron's functional deterioration in clinics. It has seriously affected the patient's cognition function, memory function, language function and space cognition function, social activities ability, personal living ability and emotion personality etc. Its cause of disease and the outbreak mechanism are still not clear. Several theories now widely recognized are: neurotransmitter impairment theory; calcium homeostasis imbalance theory; free radicals injure theory; gene mutation theory; energy dysbolism theory; nerve cell apoptosis theory; excitatory transmitter toxicity;β-Amyloid deposition theory etc. YLS, the root of one plant named Millettia pulchra Kurz var laxior (Dunn) Z.Wei, is a commonly used Chinese herb in Guangxi province. It has the function of supplying QI and blood, increasing the human ability of immunity, anti-aging, anti-stress etc. It can also make the body strong and allay tiredness so as to be applied to treat poor memory in old people and children's hypophrenia in clinics. Physically weak person, sickness person and postnatal weakness women can also be used. Our research is to extract polysaccharides from YLS and to observe the effects of YLS polysaccharides on anti-dementia and its mechanism.
1. Research on the extraction and assaying method of polysaccharides in Yulangsan
The linear range of glucose concentration was15.12-65.52μg·mL-1, and the results showed good precision, the average recovery ratio was98.25%, RSD=1.72%; By the orthogonal design of extracting conditions we found that the conditions as three hours for water-soaking time, adding ten times amount of water, three hours for extract time and extract three times had the highest extraction rate. Through the optimized extraction conditions, the higher rates and higher purity of YLSP can be extracted. Phenol-sulfuric acid method has high accuracy and stability, it can be used for determination of polysaccharides in Yulangsan.
2. Protective effects of YLSP on Aβ25-35-induced injury in PC12cells
PC12cells were treated with Aβ25-35to establish a cell model of Alzheimer's disease. The cell morphology, cell viability and proliferation, persistence, neurite outgrowth and average length were observed. The activities of SOD, GSH-Px, NOS and the contents of GSH, NO, MDA and LDH in culture supernatant and (or) cells were examined by Spectrophotometry. ROS,[Ca2+]i and MMP were examined by FCM. The results showed that LYSP could protect PC12cells from Aβ25-35neurotoxicity:the cells morphology was at good condition and the cell viability, proliferation, persistence, neurite outgrowth and average length were significantly elevated. LYSP-treated group could enhance SOD, GSH-Px activity and GSH content, decrease NOS activity and MDA, NO, ROS, LDH contents significantly in culture supernatant and (or) cells. LYSP-treated group also could decrease [Ca2+]i and increase MMP. It suggests that YLSP can protect PC12cells from injury induced by Aβ25-35.
3. Protective effects of YLSP on Aβ325-35-induced apoptosis in PC12cells
We measured PC12cell apoptosis ratio by FCM and DAPI staining, and investigated whether there are any apoptotic gene expression changes involved in the apoptosis and the effects of YLSP by real-time PCR. The results showed that PC12cell apoptosis ratio of LYSP-treated group was decreased obviously, Decrease of Bcl-2mRNA and increase of p53, Bax and Caspase-3mRNA under the treatment of AP25-35were reversed by the treatment of YLSP to PC12cells.
4. Effects of YLSP on Caspase-3expression, Caspase-3activity and Tau(Ser202) phosphorylation in the frontal lobe and hippocampus of SAMP8mouse
The SAMP8mouse was adopted as AD model group. Caspase-3expression, Caspase-3activity and Tau(Ser202) phosphorylation in the frontal lobe and hippocampus were respectively detected by immunohistochemical method. The results showed that the abnormal Caspase-3expression, Caspase-3activity and Tau(Ser202) phosphorylation were reduced by YLSP.
Based on the above results, it is concluded that LYSP have markedly protective effects on Aβ25-35-induecd injury and apoptosis by scavenging free radicals, attenuating the MMP loss, preventing the influx of Ca2+and release of LDH, up-regulating the expressions of Bcl-2mRNA, down-regulating the expressions of p53, Bax and Caspase-3mRNA and reducing Tau(Ser202) phosphorylation.
1、正交法优化YLSP提取工艺及含量测定方法的研究
葡萄糖的检测浓度在15.12-65.52μg·mL-1范围内与吸光度呈现良好的线性关系,结果精密度高,平均加样回收率为98.25%,RSD=1.72%；通过提取条件的正交试验发现,浸泡3小时、加10倍量水、提取3次,每次3小时条件下YLSP得率最高。因此,通过优化提取条件,能够提高YLSP的得率和纯度。苯酚-硫酸法准确度高、稳定性好,可作为YLSP的含量测定方法。
2、YLSP对AP25-35诱导PC12细胞损伤的保护作用
采用AP25-35诱导PC12细胞损伤作为AD细胞模型,通过MTT比色法测定分析细胞存活率；倒置相差显微镜、透射电镜观察细胞形态改变,测定细胞突起率、突起平均长度；分光光度法检测PC12细胞细胞培养液和(或)细胞内的SOD、GSH-Px和NOS活性,GSH、MDA、NO和LDH的含量；流式细胞仪测定PC12细胞内ROS、钙离子的含量及线粒体膜电位(MMP)。结果显示：Aβ25-35对PC12细胞具有明显的损伤作用,增加细胞死亡率,减少细胞突起率,缩短细胞突起长度,镜下表现出明显的凋亡损伤形态,细胞培养液和(或)细胞内的NOS活性及NO、MDA、ROS、 LDH和钙离子含量明显升高,而SOD、GSH-Px活性及GSH的含量明显降低,MMP也明显降低。YLSP能在一定程度抑制Aβ25-35对PC12细胞的损伤作用：降低细胞死亡率,增加细胞突起率,延长细胞突起长度,镜下凋亡损伤形态显著改变,细胞膜上微绒毛增多,空泡减少,明显降低PC12细胞细胞培养液和(或)细胞内的NOS活性及NO-、MDA、ROS、LDH和钙离子含量,明显提高PC12细胞细胞培养液中及细胞内SOD、GSH-Px活性及GSH的含量,明显提高MMP水平。提示YLSP可能是通过减少脂质过氧化产物的形成、增加抗氧化酶的抗氧化活性,增强细胞总的抗氧化活力而发挥抗痴呆作用。
3、YLSP对Aβ25-35诱导PC12细胞凋亡的保护作用
采用流式细胞仪、DAPI染色方法观察测定PC12细胞凋亡率,Real-time PCR测定PC12细胞凋亡相关基因p53、Bcl-2、Bax及Caspase-3mRNA表达。结果显示：Aβ25-35能明显增加PC12细胞的凋亡,促凋亡基因p53、Bax、 Caspase-3的mRNA表达含量明显升高,抑凋亡基因Bcl-2基因的mRNA表达含量明显降低。YLSP能显著减少Aβ25-35引起的PC12细胞凋亡,降低细胞凋亡率,降低促凋亡基因p53、Bax、Caspase-3的mRNA表达含量,增加抑凋亡基因Bcl-2mRNA表达含量。提示YLSP可以拮抗Aβ25-35引起的PC12细胞凋亡,逆转上述基因的表达,从而起到抗凋亡的作用。
4、YLS1'对SAMP8小鼠额叶、海马神经元Caspase-3表达及活性、Tau蛋白磷酸化的影响
采用快速老化小白鼠(senescence accelerated mouse prone8, SAMP8)作为AD动物模型,通过免疫组化的方法观察YLSP对SAMP8小鼠额叶、海马的病理变化,神经元细胞Caspase-3的表达及tau蛋白磷酸化水平的影响。结果显示：SAMP8小鼠额叶、海马神经细胞凋亡明显,Caspase-3阳性细胞数、Caspase-3活性和Tau (pSer202)阳性细胞数均明显高于SAMR1对照小鼠。YLSP能显著减少SAMP8小鼠额叶、海马神经细胞Caspase-3和Tau (pSer202)阳性细胞数,降低Caspase-3活性,提示YLSP能通过抑制凋亡,拮抗Tau (Ser202)的异常磷酸化而发挥抗痴呆的作用。
综上所述,YLSP可能是通过清除自由基、对抗氧化应激反应,减少Ca2+内流及LDH释放、提高线粒体膜电位水平,抑制p53、Bax、Caspase-3基因mRNA表达,促进Bcl-2基因的mRNA表达,拮抗Tau (Ser202)的异常磷酸化等机制而达到抗痴呆作用。本文研究认为YLSP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 is one kind of disease characterized by recent memory handicap, senile plaque(SP), neurofibrillary tangle(NFT), and neuron loss in pathology and gradually neuron's functional deterioration in clinics. It has seriously affected the patient's cognition function, memory function, language function and space cognition function, social activities ability, personal living ability and emotion personality etc. Its cause of disease and the outbreak mechanism are still not clear. Several theories now widely recognized are: neurotransmitter impairment theory; calcium homeostasis imbalance theory; free radicals injure theory; gene mutation theory; energy dysbolism theory; nerve cell apoptosis theory; excitatory transmitter toxicity;β-Amyloid deposition theory etc. YLS, the root of one plant named Millettia pulchra Kurz var laxior (Dunn) Z.Wei, is a commonly used Chinese herb in Guangxi province. It has the function of supplying QI and blood, increasing the human ability of immunity, anti-aging, anti-stress etc. It can also make the body strong and allay tiredness so as to be applied to treat poor memory in old people and children's hypophrenia in clinics. Physically weak person, sickness person and postnatal weakness women can also be used. Our research is to extract polysaccharides from YLS and to observe the effects of YLS polysaccharides on anti-dementia and its mechanism.
1. Research on the extraction and assaying method of polysaccharides in Yulangsan
The linear range of glucose concentration was15.12-65.52μg·mL-1, and the results showed good precision, the average recovery ratio was98.25%, RSD=1.72%; By the orthogonal design of extracting conditions we found that the conditions as three hours for water-soaking time, adding ten times amount of water, three hours for extract time and extract three times had the highest extraction rate. Through the optimized extraction conditions, the higher rates and higher purity of YLSP can be extracted. Phenol-sulfuric acid method has high accuracy and stability, it can be used for determination of polysaccharides in Yulangsan.
2. Protective effects of YLSP on Aβ25-35-induced injury in PC12cells
PC12cells were treated with Aβ25-35to establish a cell model of Alzheimer's disease. The cell morphology, cell viability and proliferation, persistence, neurite outgrowth and average length were observed. The activities of SOD, GSH-Px, NOS and the contents of GSH, NO, MDA and LDH in culture supernatant and (or) cells were examined by Spectrophotometry. ROS,[Ca2+]i and MMP were examined by FCM. The results showed that LYSP could protect PC12cells from Aβ25-35neurotoxicity:the cells morphology was at good condition and the cell viability, proliferation, persistence, neurite outgrowth and average length were significantly elevated. LYSP-treated group could enhance SOD, GSH-Px activity and GSH content, decrease NOS activity and MDA, NO, ROS, LDH contents significantly in culture supernatant and (or) cells. LYSP-treated group also could decrease [Ca2+]i and increase MMP. It suggests that YLSP can protect PC12cells from injury induced by Aβ25-35.
3. Protective effects of YLSP on Aβ325-35-induced apoptosis in PC12cells
We measured PC12cell apoptosis ratio by FCM and DAPI staining, and investigated whether there are any apoptotic gene expression changes involved in the apoptosis and the effects of YLSP by real-time PCR. The results showed that PC12cell apoptosis ratio of LYSP-treated group was decreased obviously, Decrease of Bcl-2mRNA and increase of p53, Bax and Caspase-3mRNA under the treatment of AP25-35were reversed by the treatment of YLSP to PC12cells.
4. Effects of YLSP on Caspase-3expression, Caspase-3activity and Tau(Ser202) phosphorylation in the frontal lobe and hippocampus of SAMP8mouse
The SAMP8mouse was adopted as AD model group. Caspase-3expression, Caspase-3activity and Tau(Ser202) phosphorylation in the frontal lobe and hippocampus were respectively detected by immunohistochemical method. The results showed that the abnormal Caspase-3expression, Caspase-3activity and Tau(Ser202) phosphorylation were reduced by YLSP.
Based on the above results, it is concluded that LYSP have markedly protective effects on Aβ25-35-induecd injury and apoptosis by scavenging free radicals, attenuating the MMP loss, preventing the influx of Ca2+and release of LDH, up-regulating the expressions of Bcl-2mRNA, down-regulating the expressions of p53, Bax and Caspase-3mRNA and reducing Tau(Ser202) phosphorylation.
引文
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