瓜子金皂苷己抑制神经细胞缺血再灌注损伤及抗神经炎症作用的体外研究
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摘要
缺血性脑血管病是临床上最常见的脑血管病，是严重危害人类健康与生存的主要疾病之一。脑缺血再恢复血供后，往往会出现缺血再灌注（ischemia-reperfusion，I/R）损伤，造成更严重的脑机能障碍，脑缺血后强烈的炎症反应也是造成脑组织继发性损伤的重要因素。因此，抗脑I/R损伤已成为脑缺血治疗中的重点，积极寻找有效的治疗药物以减轻脑I/R损伤，是降低患者死亡率和致残率的重要手段。
瓜子金是我国民间常用中药，具有祛痰、镇静、抗炎和抗抑郁的功效。瓜子金皂苷己（polygalasaponin F，PGSF)是从瓜子金中提取的三萜皂苷单体化合物，研究资料显示PGSF对神经系统具有非常广泛的药理活性，但其对脑I/R损伤影响的研究资料鲜有报道。故本课题选择I/R损伤和与之相关的神经炎症作为研究方向，旨在探讨PGSF对I/R损伤的神经细胞的保护作用及其作用机制。
首先，本文采用MTT比色法和ELISA法从多个角度对PGSF的药理活性进行了初步筛选，结果表明PGSF在体外去血清模型、H2O2氧化应激模型、低糖低氧模型、MPP+拟帕金森氏症模型中对PC12细胞均具有显著的保护作用(P<0.01, P<0.05),并可以抑制LPS诱导的BV-2小胶质细胞释放TNF-α。
然后，采用PC12和原代皮层神经元建立物理性和化学性去氧两种氧糖剥夺/复供(oxygen-glucose deprivation and reperfusion,OGD/R)模拟I/R模型，应用MTT法、显微镜照相、Hoechst33342/PI双染、流式细胞术方法，证明10、1、0.1μmol/L浓度的PGSF可提高OGD/R损伤的神经细胞的存活率，改善细胞形态和PC12细胞的细胞核形态，减轻细胞膜通透性受损程度，降低细胞的晚期凋亡/坏死百分率，提示PGSF对OGD/R损伤的神经细胞具有保护作用；进一步采用JC-1荧光染色法、DCF-DA荧光探针法及免疫印迹法证明PGSF抗I/R损伤作用的机制可能与其维持细胞线粒体膜电位、减少细胞内活性氧含量、增加受损伤细胞的Bcl-2/Bax蛋白比值、降低P53蛋白及活性Caspase-3裂解片段表达有关。
最后，建立了LPS诱导BV-2小胶质细胞神经炎症模型，从抗神经炎症的角度探讨了PGSF抗缺血再灌注损伤的作用机制。应用ELISA法检测发现，PGSF可显著抑制BV-2细胞释放TNF-α、IL-1β和NO的生成(P<0.01, P<0.05)。免疫印迹和逆转录PCR实验结果表明，PGSF可显著抑制LPS诱导的BV-2细胞iNOS和COX-2的蛋白和mRNA的表达，减少TNF-α和IL-1βmRNA的表达，并可降低LPS诱导的BV-2细胞TLR4mRNA的表达水平，提示以上PGSF抗神经炎症的效应可能是通过阻断TLR4介导的信号转导通路实现的。应用LPS刺激BV-2小胶质细胞的条件培养基对PC12细胞造成损伤的模型中，PGSF可显著提高PC12细胞存活率，在体外试验中证明了PGSF可以通过抑制小胶质细胞的激活而抑制炎症对神经细胞的损伤。
综上所述，本研究首次在体外试验中证明瓜子金皂苷己对缺血再灌注损伤的神经细胞具有明显的保护作用，并具有抗神经炎症的作用，此为PGSF的合理应用及进一步研究开发提供了重要的理论依据。
Ischemic cerebrovascular disease is the most common clinical cerebrovasculardisease and one of the main diseases threatening human health and survival.Ischemia-reperfusion（I/R) injury often appears after restoration of blood supply andresults in more severe brain dysfunction, the inflammatory reaction after cerebral ischemiais also an important factor causing the secondary brain injury. Therefore,antiischemia-reperfusion injury has become the focus in the treatment of cerebral ischemia.Looking for effective drug to relieve the cerebral I/R injury is an important means toreduce the mortality and mutilation rate.
Polygala japonica HOUTT (P japonica), a traditional Chinese medicinal herb hasbeen used as expectorant, ataractic，anti-inflammatory and antidepressant agents. Previousstudies showed that Polygalasaponin F (PGSF), a triterpenoid saponin monomer isolatedfrom Polygala japonica, has a very wide range of pharmacological activity in the nervoussystem, However, there were few reports about the research on its effects of anti-injury ofI/R in brain. So we chose I/R injury and associated neuroinflammation as the direction ofthis research in order to explore the protective effect of PGSF on neuronal cells injured byI/R and its mechanism.
First of all, preliminary screening for pharmacological activity of PGSF was carriedout by MTT colorimetry and ELISA method in several aspects. The results show thatPGSF has markedly protective effects on PC12cells in serum-free, H2O2oxidative stress,hypoxia combined with low glucose and MPP+model of Parkinson's disease in vitro(P<0.01, P<0.05), and can inhibit LPS induced BV-2microglia release of tumor necrosisfactor alpha(TNF-α).
Then, both physical and chemical oxygen-glucose deprivation and reperfusion(OGD/R) models were established in PC12cells and primary cortical neurons respectively,and MTT assay, microscope, Hoechst33342/PI dual staining and flow cytometry methodswere used to prove that PGSF at10,1or0.1μmol/L can increase the viability of cellsinjured by OGD/R, improve the cell morphology and the nuclear morphology of PC12cells, inhibit the damage of cell membrane permeability, reduce the percentage of cell lateapoptosis or necrosis, which suggests that PGSF can protect neuronal cells against OGD/Rinjury. Furthermore，JC-1fluorescent staining, DCF-DA fluorescence probe methods and Western blot were applied to prove that the mechanism of PGSF against I/R injury may berelated to maintenance of the mitochondrial membrane potential, reducing ROS production,increasing Bcl-2/Bax protein ratio in injured cells, down-regulating expression of P53protein and active Caspase-3fragment.
Finally, LPS-stimulated BV-2microglial cells neuroinflammation model was made toexplore the mechanism of PGSF antiischemia-reperfusion injury from the point of view ofthe antineuroinflammation. ELISA assay shows that PGSF can inhibit release of TNF-α,IL-1β and generation of NO in BV-2cells. Results from western blotting and reversetranscription PCR show that, PGSF can inhibit the expression of iNOS and COX-2proteinand mRNA, reduce the expression of TNF-αmRNA, IL-1β mRNA, and TLR4mRNA inBV-2cells stimulated by LPS, which suggests the antineuroinflammatory effect of PGSFmay be connected with the TLR4signal transduction pathway. In the model of PC12cells injured by LPS-stimulated BV-2microglia conditioned medium, PGSF cansignificantly increase the viability of PC12cells, which proves that PGSF can inhibit theinflammation injury to neuronal cells by inhibiting activation of microglial cells in vitro.
In summary, this study demonstrates the first time that Polygalasaponin F has asignificant protective effect on neuronal cells injured by I/R, and hasantineuroinflammatory effect in vitro, which provides an important theoretical basis forrational applications and further research and development of PGSF.
瓜子金是我国民间常用中药，具有祛痰、镇静、抗炎和抗抑郁的功效。瓜子金皂苷己（polygalasaponin F，PGSF)是从瓜子金中提取的三萜皂苷单体化合物，研究资料显示PGSF对神经系统具有非常广泛的药理活性，但其对脑I/R损伤影响的研究资料鲜有报道。故本课题选择I/R损伤和与之相关的神经炎症作为研究方向，旨在探讨PGSF对I/R损伤的神经细胞的保护作用及其作用机制。
首先，本文采用MTT比色法和ELISA法从多个角度对PGSF的药理活性进行了初步筛选，结果表明PGSF在体外去血清模型、H2O2氧化应激模型、低糖低氧模型、MPP+拟帕金森氏症模型中对PC12细胞均具有显著的保护作用(P<0.01, P<0.05),并可以抑制LPS诱导的BV-2小胶质细胞释放TNF-α。
然后，采用PC12和原代皮层神经元建立物理性和化学性去氧两种氧糖剥夺/复供(oxygen-glucose deprivation and reperfusion,OGD/R)模拟I/R模型，应用MTT法、显微镜照相、Hoechst33342/PI双染、流式细胞术方法，证明10、1、0.1μmol/L浓度的PGSF可提高OGD/R损伤的神经细胞的存活率，改善细胞形态和PC12细胞的细胞核形态，减轻细胞膜通透性受损程度，降低细胞的晚期凋亡/坏死百分率，提示PGSF对OGD/R损伤的神经细胞具有保护作用；进一步采用JC-1荧光染色法、DCF-DA荧光探针法及免疫印迹法证明PGSF抗I/R损伤作用的机制可能与其维持细胞线粒体膜电位、减少细胞内活性氧含量、增加受损伤细胞的Bcl-2/Bax蛋白比值、降低P53蛋白及活性Caspase-3裂解片段表达有关。
最后，建立了LPS诱导BV-2小胶质细胞神经炎症模型，从抗神经炎症的角度探讨了PGSF抗缺血再灌注损伤的作用机制。应用ELISA法检测发现，PGSF可显著抑制BV-2细胞释放TNF-α、IL-1β和NO的生成(P<0.01, P<0.05)。免疫印迹和逆转录PCR实验结果表明，PGSF可显著抑制LPS诱导的BV-2细胞iNOS和COX-2的蛋白和mRNA的表达，减少TNF-α和IL-1βmRNA的表达，并可降低LPS诱导的BV-2细胞TLR4mRNA的表达水平，提示以上PGSF抗神经炎症的效应可能是通过阻断TLR4介导的信号转导通路实现的。应用LPS刺激BV-2小胶质细胞的条件培养基对PC12细胞造成损伤的模型中，PGSF可显著提高PC12细胞存活率，在体外试验中证明了PGSF可以通过抑制小胶质细胞的激活而抑制炎症对神经细胞的损伤。
综上所述，本研究首次在体外试验中证明瓜子金皂苷己对缺血再灌注损伤的神经细胞具有明显的保护作用，并具有抗神经炎症的作用，此为PGSF的合理应用及进一步研究开发提供了重要的理论依据。
Ischemic cerebrovascular disease is the most common clinical cerebrovasculardisease and one of the main diseases threatening human health and survival.Ischemia-reperfusion（I/R) injury often appears after restoration of blood supply andresults in more severe brain dysfunction, the inflammatory reaction after cerebral ischemiais also an important factor causing the secondary brain injury. Therefore,antiischemia-reperfusion injury has become the focus in the treatment of cerebral ischemia.Looking for effective drug to relieve the cerebral I/R injury is an important means toreduce the mortality and mutilation rate.
Polygala japonica HOUTT (P japonica), a traditional Chinese medicinal herb hasbeen used as expectorant, ataractic，anti-inflammatory and antidepressant agents. Previousstudies showed that Polygalasaponin F (PGSF), a triterpenoid saponin monomer isolatedfrom Polygala japonica, has a very wide range of pharmacological activity in the nervoussystem, However, there were few reports about the research on its effects of anti-injury ofI/R in brain. So we chose I/R injury and associated neuroinflammation as the direction ofthis research in order to explore the protective effect of PGSF on neuronal cells injured byI/R and its mechanism.
First of all, preliminary screening for pharmacological activity of PGSF was carriedout by MTT colorimetry and ELISA method in several aspects. The results show thatPGSF has markedly protective effects on PC12cells in serum-free, H2O2oxidative stress,hypoxia combined with low glucose and MPP+model of Parkinson's disease in vitro(P<0.01, P<0.05), and can inhibit LPS induced BV-2microglia release of tumor necrosisfactor alpha(TNF-α).
Then, both physical and chemical oxygen-glucose deprivation and reperfusion(OGD/R) models were established in PC12cells and primary cortical neurons respectively,and MTT assay, microscope, Hoechst33342/PI dual staining and flow cytometry methodswere used to prove that PGSF at10,1or0.1μmol/L can increase the viability of cellsinjured by OGD/R, improve the cell morphology and the nuclear morphology of PC12cells, inhibit the damage of cell membrane permeability, reduce the percentage of cell lateapoptosis or necrosis, which suggests that PGSF can protect neuronal cells against OGD/Rinjury. Furthermore，JC-1fluorescent staining, DCF-DA fluorescence probe methods and Western blot were applied to prove that the mechanism of PGSF against I/R injury may berelated to maintenance of the mitochondrial membrane potential, reducing ROS production,increasing Bcl-2/Bax protein ratio in injured cells, down-regulating expression of P53protein and active Caspase-3fragment.
Finally, LPS-stimulated BV-2microglial cells neuroinflammation model was made toexplore the mechanism of PGSF antiischemia-reperfusion injury from the point of view ofthe antineuroinflammation. ELISA assay shows that PGSF can inhibit release of TNF-α,IL-1β and generation of NO in BV-2cells. Results from western blotting and reversetranscription PCR show that, PGSF can inhibit the expression of iNOS and COX-2proteinand mRNA, reduce the expression of TNF-αmRNA, IL-1β mRNA, and TLR4mRNA inBV-2cells stimulated by LPS, which suggests the antineuroinflammatory effect of PGSFmay be connected with the TLR4signal transduction pathway. In the model of PC12cells injured by LPS-stimulated BV-2microglia conditioned medium, PGSF cansignificantly increase the viability of PC12cells, which proves that PGSF can inhibit theinflammation injury to neuronal cells by inhibiting activation of microglial cells in vitro.
In summary, this study demonstrates the first time that Polygalasaponin F has asignificant protective effect on neuronal cells injured by I/R, and hasantineuroinflammatory effect in vitro, which provides an important theoretical basis forrational applications and further research and development of PGSF.
引文
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