神经元细胞周期调控异常在帕金森病发病机制中作用的研究
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摘要
目的建立PD细胞模型,并观察各种PD相关损伤因素对神经元样PC12细胞周期分布的影响。
方法体外培养神经元样PC12细胞,分别用不同浓度的多巴胺神经毒素(6-OHDA、MPP+和lactacystin)处理细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,并观察细胞周期抑制药物flavopiridol对细胞周期、细胞活性和细胞凋亡的影响。
结果PC12细胞经神经生长因子诱导后具有神经元的表型,各种神经毒素处理后细胞活性呈浓度依赖性和时间依赖性下降,10μM lactacystin、75μM MPP+和100μM6-OHDA使PC12细胞活力分别下降到对照组的49.31±3.23%、59.75±6.50%和48.32±9.43%。流式细胞术检测发现细胞死亡的主要方式为凋亡,且细胞凋亡率随各种神经毒素处理时间的延长而升高。细胞周期检测发现,神经元样PC12细胞71.27%处于G0/G1期,各种神经毒素处理后,G0/G1期细胞比例减少,而S期和G2/M期细胞比例升高。细胞周期抑制剂flavopiridol能够抑制细胞周期重启和细胞损伤。
结论线粒体功能障碍、氧化应激和泛素-蛋白酶体功能障碍等PD相关损伤因素能够诱导神经元细胞周期重启,细胞周期重启参与神经元损伤过程。
目的观察各种PD相关损伤因素对神经元样PC12细胞周期调节因子表达的影响。
方法体外培养神经元样PC12细胞,分别用lactacystin (10μM)、6-OHDA (100μM)和MPP+(75μM)处理细胞,逆转录聚合酶链反应(RT-PCR)观察细胞周期调节因子cyclin (cyclin A、cyclin D1、cyclin B1和cyclin E)和CDK(CDK2、CDK4和CDK1)mRNA表达水平的变化,Western blot和免疫细胞化学染色观察细胞周期调节因子pRB、p-pRB、cyclin B1、CDK4和CDK1蛋白表达水平的变化。
结果RT-PCR结果显示,各种多巴胺神经毒素处理后,神经元样PC12细胞cyclin A、cyclin D1和CDK1 mRNA表达水平升高,而cyclin B1、cyclin E、CDK2和CDK4 mRNA水平无明显改变。Western blot和免疫细胞化学染色显示,lactacystin处理后PC12细胞内pRB蛋白磷酸化水平增高,同时cyclin B1、CDK1和CDK4蛋白表达水平增高。结论各种多巴胺神经毒素通过上调细胞周期调节因子的表达(cyclin A、cyclin D1和CDK1)或抑制其降解(cyclin B1和CDK4)促进神经元细胞周期重启。
目的探讨神经元细胞周期重启后的DNA复制机制及其在神经变性中的作用。
方法MPP+处理原代培养的小脑颗粒细胞;CGCs),MTT法检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,BrdU掺入法检测S期细胞比例,Western blot法检测细胞周期调节因子(cyclin A和cyclin B)和各种DNA聚合酶(DNA pols)表达水平的变化,并观察细胞周期抑制剂(flavopiridol和olomoucine)和各种DNA pols抑制剂对细胞活性的影响,细胞内转染dominant negative DNA pol-β,观察其对细胞活性和细胞凋亡的影响。
结果MPP+处理后原代CGCs细胞活性下降和细胞凋亡,同时CGCs细胞周期重启,S期细胞增多,S期相关调节因子cyclin A表达增高,而G2/M期相关调节因子cyclin B表达水平无明显变化。细胞周期抑制剂flavopiridol和olomoucine都能够抑制MPP+引起的细胞周期重启和细胞凋亡。MPP+处理后DNA pol-β和DNA引物酶表达升高,而DNA pol-β和pol-ε表达无明显变化。DNA pol-α/δ抑制剂阿非迪霉素对细胞活性和细胞凋亡率无明显影响,而DNA pol-β抑制剂双脱氧胞苷能够抑制MPP+诱导的细胞损伤,细胞内表达dominant negative DNA pol-β也能够抑制MPP+引起的细胞活性下降和细胞凋亡。
结论神经元细胞周期重启后由DNA pol-β介导DNA复制和细胞损伤。
目的观察MAPK信号通路在MPP+诱导的PC12细胞周期重启和细胞损伤中的作用。
方法MPP+处理神经元样PC12细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,Western blot法观察ERK1/2、JNK和P38信号通路活化状态。分别使用ERK1/2通路抑制剂(PD98059)、JNK通路抑制剂(SP600125)和P38通路抑制剂(SB202190)预处理PC12细胞,观察其对神经元细胞周期和细胞活性的影响。
结果MPP+处理后PC12细胞内ERK1/2、JNK和P38磷酸化水平均增高,ERK1/2通路抑制剂PD98059能够抑制ERK1/2通路活化水平,同时能够抑制细胞周期重启和细胞活性下降。JNK通路抑制剂SP600125能够抑制细胞活性下降,但对细胞周期无明显影响。P38通路抑制剂SB202190对细胞活性和细胞周期均无显著影响。
结论ERK1/2信号通路是介导细胞周期重启的上游机制。
目的观察氧化应激在ERK1/2通路活化和细胞周期重启中的作用。
方法MPP+处理神经元样PC12细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,PI单标流式细胞术检测细胞周期分布,荧光比色法检测细胞内活性氧物质(ROS)水平,Western blot法检测ERK1/2信号通路活化状态。并观察过氧化氢酶预处理对ERK1/2通路活化、细胞周期重启和细胞活性的影响。
结果MPP+处理后PC12细胞内ROS水平增高,过氧化氢酶预处理能够抑制细胞内ROS水平升高,同时能够抑制MPP+诱导的ERK1/2通路活化、细胞周期重启和细胞活性下降。
结论氧化应激能够诱导ERK1/2信号通路活化和细胞周期重启。
目的观察桑黄素在PD细胞模型和动物模型中的神经保护作用及其机制。
方法MPP+处理神经元样PC12细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,荧光比色法检测细胞内活性氧物质(ROS)水平。MPTP腹腔注射建立小鼠PD模型,高效液相色谱法检测纹状体多巴胺水平,酪氨酸羟化酶(TH)免疫组织化学染色检测黑质多巴胺能神经元数量。
结果MPP+处理后神经元样PC12细胞活性下降,细胞内ROS水平增高,同时出现细胞周期重启,桑黄素能够明显抑制MPP+诱导的细胞活性下降、细胞凋亡和细胞内ROS水平升高,同时还能够抑制MPP+引起的细胞周期重启。MPTP小鼠模型纹状体内多巴胺水平下降,黑质多巴胺能神经元减少,桑黄素腹腔注射能够明显升高PD小鼠模型纹状体多巴胺水平,同时黑质内多巴胺能神经元数量增多。
结论桑黄素对PD细胞模型和动物模型都具有明显的神经保护作用,其保护作用的机制可能与其抗氧化、抗增殖活性有关。
Objective To investigate the role of cell cycle aberrant in neuronal death induced by dopaminergic neurotoxins.
Methods Neuronal PC12 cells were exposed to dopaminergic neurotoxins (lactacystin, MPP+, and 6-OHDA). Cell viability was measured by MTT. Flow cytometry was used to detect cell apoptosis and the distribution of cell cycle. The role of cell cycle inhibitors was assessed by MTT and flow cytometry.
Results After differentiated by NGF, PC12 cells acquire a neuronal phenotype similar to that of sympathetic neurons. The cell viability of neuronal PC12 cells decreased in a time-and concentration-dependent manner. After exposure to lactacystin, MPP+, and 6-OHDA, the apoptotic rate increased in a time-dependent manner. At the same time, the percentage of cells in G0/G1 phase of cell cycle decreased and that in G2/M phase increased. Flavopiridol, a cell cycle inhibitor attenuated the cell cycle re-entry and cell injury induced by neurotoxins.
Conclusion Cell cycle aberrant mediates cell apoptosis induced by dopaminergic neurotoxins.
Objective To investigate effect of dopaminergic neurotoxins on the expression of cell cycle regulators in neuronal PC 12 cells.
Methods Neuronal PC12 cells were exposed to dopaminergic neurotoxins (lactacystin, MPP+, and 6-OHDA). The mRNA levels of cyclin (cyclin A, cyclin D1, cyclin B1 and cyclin E) and cyclin dependent kinases (CDK2, CDK4 and CDK1) was assayed by RT-PCR. The protein levels of cell cycle regulators (pRB, p-pRB, cyclin B1, CDK4 and CDK1) were assessed by Western blot and immunocytochemistry.
Results After exposure to dopaminergic neurotoxins, the mRNA levels of cyclin A, cyclin Dl and CDK1 increased, while the mRNA levels of cyclin B1, cyclin E, CDK2 and CDK4 did not change. The protein levels of p-pRB, cyclin B1, CDK4 and CDK1 increased after exposure lactacystin.
Conclusion Neurotoxins induce cell cycle re-entry via influencing the expression and degradation cell cycle regulators.
Objective To investigate the role of DNA polymerases in DNA replication and apoptotic death in neurons after re-entering the cell cycle
Methods Cerebellar granule cells were exposed to MPP+. Cell viability was measured by MTT. Cell cycle distribution of neurons was measured by flow cytometry, and cell apoptosis was detected by flow cytometry and Hoechst staining. BrdU incorporation was used to detect the cells in S phase of cell cycle. Western blot was used to detect the expression of cyclin A, cyclin B, DNA primase, DNA pol-P, DNA pol-8 and pol-s. The effect of cell cycle inhibitors and DNA pols inhibitors on cell cycle, cell viability and cell apoptosis was assessed as well.
Results After exposure to MPP+, some of the postmitotic neurons re-entered S phase of the cell cycle. The neuronal cell cycle re-entry and apoptosis were attenuated by flavopiridol, which is a broad inhibitor of cyclin-dependent kinases (CDKs). MPP+ exposure significantly increased the expression of DNA pol-βand primase but did not affect the expression of the canonical replicative DNA pols, including DNA pol-δand pol-ε. Dideoxycytidine, which is a pharmacological inhibitor of DNA pol-β, attenuated the neuronal apoptosis mediated by MPP+. In a similar manner, the expression of a dominant negative form of DNA pol-P was also neuroprotective.
Conclusion DNA pol-βmay have a causal role in MPP+-induced neuronal apoptosis.
Objective To investigate the role of MAPK signaling pathway in cell cycle re-entry and cell injury.
Methods Neuronal PC12 cells were exposed to MPP+. Cell viability was measured by MTT. Flow cytometry was used to detect the distribution of cell cycle. Western blot was used to detect the expression of ERK, p-ERK, JNK, p-JNK, P38 and p-P38. The specific inhibitors of ERK, JNK, and P38 pathway was used to determine the role of different MAPK signaling pathway in cell cycle re-entry and cell viability.
Results After exposure to MPP+, the expression of p-ERK, p-JNK, and p-P38 increased. PD98059, an inhibitor of ERK1/2 pathway inhibited the cell cycle re-entry and cell viability lose induced by MPP+. SP600125, an inhibitor of JNK pathway attenuated cell viability loss of PC 12 cells, but did not affected the cell cycle re-entry. SB202190, an inhibitor of P38 pathway did not affect the cell viability and cell cycle re-entry.
Conclusion ERK1/2 signaling pathway mediates cell cycle re-entry induced by MPP+.
Objective To investigate the role of oxidative stress in the activation of ERK1/2 pathway in and cell cycle re-entry.
Methods Neuronal PC12 cells were exposed to MPP+. Cell viability was measured by MTT. Flow cytometry was used to detect the distribution of cell cycle. Intracellular reactive oxygen species (ROS) was measured using the fluorescent probe 2,7-dichlorofluorescein diacetate (H2DCFDA). Western blot was used to detect the expression of ERK1/2 and p-ERK. Catalase, an antioxidant was used to determine the role of oxidative stress in the activation of ERK1/2 pathway and cell cycle re-entry.
Results After exposure MPP+, the level of intracellular ROS increased, and the cells re-entered the cell cycle. Pretreatment with catalase attenuated the ROS formation, cell cycle re-entry and cell viability loss induced by MPP+.
Conclusion Oxidative stress mediates the activation of ERK1/2 pathway in and neuronal cell cycle re-entry.
Aim:To investigate the neuroprotective effects of morin on 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis in neuronal differentiated PC12 cells as well as in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.
Methods:Neuronal differentiated PC 12 cells were challenged with MPP+ in the presence or absence of morin. Cell viability was determined by the MTT method. Cell apoptosis and cell cycle distribution were measured by flow cytometry. Intracellular ROS formation was assayed by fluorescence assay. In the MPTP mouse model of PD, the striatal dopamine content was detected by HPLC. The survival of dopaminergic neurons were measured by immunohistochemistry.
Results:MPP+ induced loss of cell viability and apoptosis in neuronal PC12 cells. Concomitant treatment with morin significantly attenuated cell viability loss, apoptosis, and oxidative stress induced by MPP+. Furthermore, morin attenuated cell cycle re-entry induced by MPP+. In mice, MPTP induced significant nigrostriatal lesions. When administered prior to MPTP, morin attenuated behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model.
Conclusion:Morin is neuroprotective both in vitro and in vivo. The neuroprotective effect of morin may be attributed to its antioxidant and antiproliferative properties.
方法体外培养神经元样PC12细胞,分别用不同浓度的多巴胺神经毒素(6-OHDA、MPP+和lactacystin)处理细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,并观察细胞周期抑制药物flavopiridol对细胞周期、细胞活性和细胞凋亡的影响。
结果PC12细胞经神经生长因子诱导后具有神经元的表型,各种神经毒素处理后细胞活性呈浓度依赖性和时间依赖性下降,10μM lactacystin、75μM MPP+和100μM6-OHDA使PC12细胞活力分别下降到对照组的49.31±3.23%、59.75±6.50%和48.32±9.43%。流式细胞术检测发现细胞死亡的主要方式为凋亡,且细胞凋亡率随各种神经毒素处理时间的延长而升高。细胞周期检测发现,神经元样PC12细胞71.27%处于G0/G1期,各种神经毒素处理后,G0/G1期细胞比例减少,而S期和G2/M期细胞比例升高。细胞周期抑制剂flavopiridol能够抑制细胞周期重启和细胞损伤。
结论线粒体功能障碍、氧化应激和泛素-蛋白酶体功能障碍等PD相关损伤因素能够诱导神经元细胞周期重启,细胞周期重启参与神经元损伤过程。
目的观察各种PD相关损伤因素对神经元样PC12细胞周期调节因子表达的影响。
方法体外培养神经元样PC12细胞,分别用lactacystin (10μM)、6-OHDA (100μM)和MPP+(75μM)处理细胞,逆转录聚合酶链反应(RT-PCR)观察细胞周期调节因子cyclin (cyclin A、cyclin D1、cyclin B1和cyclin E)和CDK(CDK2、CDK4和CDK1)mRNA表达水平的变化,Western blot和免疫细胞化学染色观察细胞周期调节因子pRB、p-pRB、cyclin B1、CDK4和CDK1蛋白表达水平的变化。
结果RT-PCR结果显示,各种多巴胺神经毒素处理后,神经元样PC12细胞cyclin A、cyclin D1和CDK1 mRNA表达水平升高,而cyclin B1、cyclin E、CDK2和CDK4 mRNA水平无明显改变。Western blot和免疫细胞化学染色显示,lactacystin处理后PC12细胞内pRB蛋白磷酸化水平增高,同时cyclin B1、CDK1和CDK4蛋白表达水平增高。结论各种多巴胺神经毒素通过上调细胞周期调节因子的表达(cyclin A、cyclin D1和CDK1)或抑制其降解(cyclin B1和CDK4)促进神经元细胞周期重启。
目的探讨神经元细胞周期重启后的DNA复制机制及其在神经变性中的作用。
方法MPP+处理原代培养的小脑颗粒细胞;CGCs),MTT法检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,BrdU掺入法检测S期细胞比例,Western blot法检测细胞周期调节因子(cyclin A和cyclin B)和各种DNA聚合酶(DNA pols)表达水平的变化,并观察细胞周期抑制剂(flavopiridol和olomoucine)和各种DNA pols抑制剂对细胞活性的影响,细胞内转染dominant negative DNA pol-β,观察其对细胞活性和细胞凋亡的影响。
结果MPP+处理后原代CGCs细胞活性下降和细胞凋亡,同时CGCs细胞周期重启,S期细胞增多,S期相关调节因子cyclin A表达增高,而G2/M期相关调节因子cyclin B表达水平无明显变化。细胞周期抑制剂flavopiridol和olomoucine都能够抑制MPP+引起的细胞周期重启和细胞凋亡。MPP+处理后DNA pol-β和DNA引物酶表达升高,而DNA pol-β和pol-ε表达无明显变化。DNA pol-α/δ抑制剂阿非迪霉素对细胞活性和细胞凋亡率无明显影响,而DNA pol-β抑制剂双脱氧胞苷能够抑制MPP+诱导的细胞损伤,细胞内表达dominant negative DNA pol-β也能够抑制MPP+引起的细胞活性下降和细胞凋亡。
结论神经元细胞周期重启后由DNA pol-β介导DNA复制和细胞损伤。
目的观察MAPK信号通路在MPP+诱导的PC12细胞周期重启和细胞损伤中的作用。
方法MPP+处理神经元样PC12细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,Western blot法观察ERK1/2、JNK和P38信号通路活化状态。分别使用ERK1/2通路抑制剂(PD98059)、JNK通路抑制剂(SP600125)和P38通路抑制剂(SB202190)预处理PC12细胞,观察其对神经元细胞周期和细胞活性的影响。
结果MPP+处理后PC12细胞内ERK1/2、JNK和P38磷酸化水平均增高,ERK1/2通路抑制剂PD98059能够抑制ERK1/2通路活化水平,同时能够抑制细胞周期重启和细胞活性下降。JNK通路抑制剂SP600125能够抑制细胞活性下降,但对细胞周期无明显影响。P38通路抑制剂SB202190对细胞活性和细胞周期均无显著影响。
结论ERK1/2信号通路是介导细胞周期重启的上游机制。
目的观察氧化应激在ERK1/2通路活化和细胞周期重启中的作用。
方法MPP+处理神经元样PC12细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,PI单标流式细胞术检测细胞周期分布,荧光比色法检测细胞内活性氧物质(ROS)水平,Western blot法检测ERK1/2信号通路活化状态。并观察过氧化氢酶预处理对ERK1/2通路活化、细胞周期重启和细胞活性的影响。
结果MPP+处理后PC12细胞内ROS水平增高,过氧化氢酶预处理能够抑制细胞内ROS水平升高,同时能够抑制MPP+诱导的ERK1/2通路活化、细胞周期重启和细胞活性下降。
结论氧化应激能够诱导ERK1/2信号通路活化和细胞周期重启。
目的观察桑黄素在PD细胞模型和动物模型中的神经保护作用及其机制。
方法MPP+处理神经元样PC12细胞,四甲基偶氮唑盐法(MTT法)检测细胞活性,Annexin-V/PI双标流式细胞术检测细胞凋亡率,PI单标流式细胞术检测细胞周期分布,荧光比色法检测细胞内活性氧物质(ROS)水平。MPTP腹腔注射建立小鼠PD模型,高效液相色谱法检测纹状体多巴胺水平,酪氨酸羟化酶(TH)免疫组织化学染色检测黑质多巴胺能神经元数量。
结果MPP+处理后神经元样PC12细胞活性下降,细胞内ROS水平增高,同时出现细胞周期重启,桑黄素能够明显抑制MPP+诱导的细胞活性下降、细胞凋亡和细胞内ROS水平升高,同时还能够抑制MPP+引起的细胞周期重启。MPTP小鼠模型纹状体内多巴胺水平下降,黑质多巴胺能神经元减少,桑黄素腹腔注射能够明显升高PD小鼠模型纹状体多巴胺水平,同时黑质内多巴胺能神经元数量增多。
结论桑黄素对PD细胞模型和动物模型都具有明显的神经保护作用,其保护作用的机制可能与其抗氧化、抗增殖活性有关。
Objective To investigate the role of cell cycle aberrant in neuronal death induced by dopaminergic neurotoxins.
Methods Neuronal PC12 cells were exposed to dopaminergic neurotoxins (lactacystin, MPP+, and 6-OHDA). Cell viability was measured by MTT. Flow cytometry was used to detect cell apoptosis and the distribution of cell cycle. The role of cell cycle inhibitors was assessed by MTT and flow cytometry.
Results After differentiated by NGF, PC12 cells acquire a neuronal phenotype similar to that of sympathetic neurons. The cell viability of neuronal PC12 cells decreased in a time-and concentration-dependent manner. After exposure to lactacystin, MPP+, and 6-OHDA, the apoptotic rate increased in a time-dependent manner. At the same time, the percentage of cells in G0/G1 phase of cell cycle decreased and that in G2/M phase increased. Flavopiridol, a cell cycle inhibitor attenuated the cell cycle re-entry and cell injury induced by neurotoxins.
Conclusion Cell cycle aberrant mediates cell apoptosis induced by dopaminergic neurotoxins.
Objective To investigate effect of dopaminergic neurotoxins on the expression of cell cycle regulators in neuronal PC 12 cells.
Methods Neuronal PC12 cells were exposed to dopaminergic neurotoxins (lactacystin, MPP+, and 6-OHDA). The mRNA levels of cyclin (cyclin A, cyclin D1, cyclin B1 and cyclin E) and cyclin dependent kinases (CDK2, CDK4 and CDK1) was assayed by RT-PCR. The protein levels of cell cycle regulators (pRB, p-pRB, cyclin B1, CDK4 and CDK1) were assessed by Western blot and immunocytochemistry.
Results After exposure to dopaminergic neurotoxins, the mRNA levels of cyclin A, cyclin Dl and CDK1 increased, while the mRNA levels of cyclin B1, cyclin E, CDK2 and CDK4 did not change. The protein levels of p-pRB, cyclin B1, CDK4 and CDK1 increased after exposure lactacystin.
Conclusion Neurotoxins induce cell cycle re-entry via influencing the expression and degradation cell cycle regulators.
Objective To investigate the role of DNA polymerases in DNA replication and apoptotic death in neurons after re-entering the cell cycle
Methods Cerebellar granule cells were exposed to MPP+. Cell viability was measured by MTT. Cell cycle distribution of neurons was measured by flow cytometry, and cell apoptosis was detected by flow cytometry and Hoechst staining. BrdU incorporation was used to detect the cells in S phase of cell cycle. Western blot was used to detect the expression of cyclin A, cyclin B, DNA primase, DNA pol-P, DNA pol-8 and pol-s. The effect of cell cycle inhibitors and DNA pols inhibitors on cell cycle, cell viability and cell apoptosis was assessed as well.
Results After exposure to MPP+, some of the postmitotic neurons re-entered S phase of the cell cycle. The neuronal cell cycle re-entry and apoptosis were attenuated by flavopiridol, which is a broad inhibitor of cyclin-dependent kinases (CDKs). MPP+ exposure significantly increased the expression of DNA pol-βand primase but did not affect the expression of the canonical replicative DNA pols, including DNA pol-δand pol-ε. Dideoxycytidine, which is a pharmacological inhibitor of DNA pol-β, attenuated the neuronal apoptosis mediated by MPP+. In a similar manner, the expression of a dominant negative form of DNA pol-P was also neuroprotective.
Conclusion DNA pol-βmay have a causal role in MPP+-induced neuronal apoptosis.
Objective To investigate the role of MAPK signaling pathway in cell cycle re-entry and cell injury.
Methods Neuronal PC12 cells were exposed to MPP+. Cell viability was measured by MTT. Flow cytometry was used to detect the distribution of cell cycle. Western blot was used to detect the expression of ERK, p-ERK, JNK, p-JNK, P38 and p-P38. The specific inhibitors of ERK, JNK, and P38 pathway was used to determine the role of different MAPK signaling pathway in cell cycle re-entry and cell viability.
Results After exposure to MPP+, the expression of p-ERK, p-JNK, and p-P38 increased. PD98059, an inhibitor of ERK1/2 pathway inhibited the cell cycle re-entry and cell viability lose induced by MPP+. SP600125, an inhibitor of JNK pathway attenuated cell viability loss of PC 12 cells, but did not affected the cell cycle re-entry. SB202190, an inhibitor of P38 pathway did not affect the cell viability and cell cycle re-entry.
Conclusion ERK1/2 signaling pathway mediates cell cycle re-entry induced by MPP+.
Objective To investigate the role of oxidative stress in the activation of ERK1/2 pathway in and cell cycle re-entry.
Methods Neuronal PC12 cells were exposed to MPP+. Cell viability was measured by MTT. Flow cytometry was used to detect the distribution of cell cycle. Intracellular reactive oxygen species (ROS) was measured using the fluorescent probe 2,7-dichlorofluorescein diacetate (H2DCFDA). Western blot was used to detect the expression of ERK1/2 and p-ERK. Catalase, an antioxidant was used to determine the role of oxidative stress in the activation of ERK1/2 pathway and cell cycle re-entry.
Results After exposure MPP+, the level of intracellular ROS increased, and the cells re-entered the cell cycle. Pretreatment with catalase attenuated the ROS formation, cell cycle re-entry and cell viability loss induced by MPP+.
Conclusion Oxidative stress mediates the activation of ERK1/2 pathway in and neuronal cell cycle re-entry.
Aim:To investigate the neuroprotective effects of morin on 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis in neuronal differentiated PC12 cells as well as in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.
Methods:Neuronal differentiated PC 12 cells were challenged with MPP+ in the presence or absence of morin. Cell viability was determined by the MTT method. Cell apoptosis and cell cycle distribution were measured by flow cytometry. Intracellular ROS formation was assayed by fluorescence assay. In the MPTP mouse model of PD, the striatal dopamine content was detected by HPLC. The survival of dopaminergic neurons were measured by immunohistochemistry.
Results:MPP+ induced loss of cell viability and apoptosis in neuronal PC12 cells. Concomitant treatment with morin significantly attenuated cell viability loss, apoptosis, and oxidative stress induced by MPP+. Furthermore, morin attenuated cell cycle re-entry induced by MPP+. In mice, MPTP induced significant nigrostriatal lesions. When administered prior to MPTP, morin attenuated behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model.
Conclusion:Morin is neuroprotective both in vitro and in vivo. The neuroprotective effect of morin may be attributed to its antioxidant and antiproliferative properties.
引文
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