7，8-二羟基黄酮对6-羟基多巴胺诱导的PC12细胞损伤的保护作用研究
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摘要
为研究7,8-二羟基黄酮(7,8-Dihydroxyflavone,7,8-DHF)对抗6-羟基多巴胺(6-Hydroxydopamine,6-OHDA)毒性作用的分子机制,本研究应用6-OHDA诱导PC12细胞损伤,采用MTT法,观察7,8-DHF对PC12细胞的保护作用并用酪氨酸激酶(tyrosine kinase B, TrKB)受体阻断剂ANA-12、K252a和磷脂酰肌醇3位羟基激酶(phosphatidylinositol-3 kinase, PI3K)抑制剂LY294002对PC12细胞保护作用的阻断效应。并采用Hoechst 33258染色、flow cytometry、RT-PCR、酶标法等多种实验方法,观察PC12细胞的凋亡,TrKB受体的表达和7,8-DHF的自身抗氧化性等来探讨7,8-DHF对PC12细胞的保护作用机制。实验结果如下：
16-OHDA可剂量依赖式降低PC12细胞的存活率(P<0.001)；7,8-DHF可减弱6-OHDA对PC12细胞的毒性作用(P<0.001),并且7,8-DHF在25μM浓度时保护作用最明显。
2 7,8-DHF对抗6-OHDA的毒性作用可以被PI3K抑制剂LY294002阻断(P<0.001)。
36-OHDA可明显导致PC12细胞的凋亡(P<0.001),而7,8-DHF可明显降低PC12细胞的凋亡率(P<0.001)
46-OHDA可明显降低PC12细胞的线粒体膜电位(P<0.01),而7,8-DHF可明显逆转上述改变(P<0.01)
56-OHDA可以明显升高细胞脂质过氧化物丙二醛(MDA)含量(p<0.05),而7,8-DHF预保护可以抑制6-OHDA诱导的MDA升高(P<0.05)。
6 7,8-DHF可以明显增加超氧化物歧化酶(SOD)的活性(p<0.01),而经6-OHDA处理的细胞SOD没有明显变化(p>0.05)
以上结果表明7,8-DHF可明显对抗6-OHDA对PC12细胞的损伤,其机制可能与7,8-DHF抑制细胞凋亡,激活PI3K/Akt信号通路以及其自身的抗氧化性有关。本研究不仅为7,8-DHF的神经保护作用机制提供了进一步的实验依据,而且为进一步开发为可用于临床防治帕金森病的新药提供实验依据。
The present study aims at investigating the protective effects of 7,8-DHF against the toxicity of 6-OHDA and the molecular mechanism.In this research,we used 6-OHDA to injure PC 12 cells.MTT was used to observe the protective effects of 7,8-DHF against 6-OHDA and the blocking effects of tyrosine TrKB antagonist ANA-12,K252a and PI3K antagonist LY294002.Moreover, Hoechst 33258 staining,Reverse translation-PCR, flow cytometry and enzyme linked immunosorbent assay were used to observe the apoptosis of PC12 cells,the expression of TrKB and the self-anti-oxidative stability.Results are as follows:
1. 6-OHDA decreased cell viability of PC12 in a dose-dependent manner(P<0.001). 7,8-DHF attenuated the toxicity of 6-OHDA(P< 0.001).The maximal rescue occurred at the concentration of 25μM.
2. The neuroprotective effect of 7,8-DHF on cell viability against 6-OHDA-induced toxicity was completely blocked by LY294002 (P<0.001)
3. 6-OHDA can significantly induce the apoptosis of PC 12 cells (P< 0.001),7,8-DHF attenuated the apoptostic rate of PC12 cells induced by 6-OHDA(P<0.001).
4. 6-OHDA significantly decreased mitochondrial membrance potential in PC12 cells(P <0.01).7,8-DHF could significantly reverse the toxic effects of 6-OHDA (P< 0.01)
5. 6-OHDA significantly caused the increase of Malondialdehyde (MDA) (P< 0.05).Treatment with 7,8-DHF preliminarily increased the quantity of MDA controlled with the 6-OHDA group(P<0.05).
6. Treatment with 7,8-DHF preliminarily can significantly cause the increase of Superoxide Dismutase(SOD) activity (P<0.01)
These data demonstrated that 7,8-DHF have neuroprotective effects against the 6-OHDA-induced neurotoxicity in PC 12 cells and their actions might involve inhibiting PC12 cells apoptosis,activation of PI3K/Akt signaling pathways and the self-anti-oxidative stability of 7,8-DHF.These results not only provide new mechanism for the neuroprotective effects of 7,8-DHF,but also provide experimental evidence for the clinical application of 7,8-DHF for prevention and treatment of Parkinson'disease.
16-OHDA可剂量依赖式降低PC12细胞的存活率(P<0.001)；7,8-DHF可减弱6-OHDA对PC12细胞的毒性作用(P<0.001),并且7,8-DHF在25μM浓度时保护作用最明显。
2 7,8-DHF对抗6-OHDA的毒性作用可以被PI3K抑制剂LY294002阻断(P<0.001)。
36-OHDA可明显导致PC12细胞的凋亡(P<0.001),而7,8-DHF可明显降低PC12细胞的凋亡率(P<0.001)
46-OHDA可明显降低PC12细胞的线粒体膜电位(P<0.01),而7,8-DHF可明显逆转上述改变(P<0.01)
56-OHDA可以明显升高细胞脂质过氧化物丙二醛(MDA)含量(p<0.05),而7,8-DHF预保护可以抑制6-OHDA诱导的MDA升高(P<0.05)。
6 7,8-DHF可以明显增加超氧化物歧化酶(SOD)的活性(p<0.01),而经6-OHDA处理的细胞SOD没有明显变化(p>0.05)
以上结果表明7,8-DHF可明显对抗6-OHDA对PC12细胞的损伤,其机制可能与7,8-DHF抑制细胞凋亡,激活PI3K/Akt信号通路以及其自身的抗氧化性有关。本研究不仅为7,8-DHF的神经保护作用机制提供了进一步的实验依据,而且为进一步开发为可用于临床防治帕金森病的新药提供实验依据。
The present study aims at investigating the protective effects of 7,8-DHF against the toxicity of 6-OHDA and the molecular mechanism.In this research,we used 6-OHDA to injure PC 12 cells.MTT was used to observe the protective effects of 7,8-DHF against 6-OHDA and the blocking effects of tyrosine TrKB antagonist ANA-12,K252a and PI3K antagonist LY294002.Moreover, Hoechst 33258 staining,Reverse translation-PCR, flow cytometry and enzyme linked immunosorbent assay were used to observe the apoptosis of PC12 cells,the expression of TrKB and the self-anti-oxidative stability.Results are as follows:
1. 6-OHDA decreased cell viability of PC12 in a dose-dependent manner(P<0.001). 7,8-DHF attenuated the toxicity of 6-OHDA(P< 0.001).The maximal rescue occurred at the concentration of 25μM.
2. The neuroprotective effect of 7,8-DHF on cell viability against 6-OHDA-induced toxicity was completely blocked by LY294002 (P<0.001)
3. 6-OHDA can significantly induce the apoptosis of PC 12 cells (P< 0.001),7,8-DHF attenuated the apoptostic rate of PC12 cells induced by 6-OHDA(P<0.001).
4. 6-OHDA significantly decreased mitochondrial membrance potential in PC12 cells(P <0.01).7,8-DHF could significantly reverse the toxic effects of 6-OHDA (P< 0.01)
5. 6-OHDA significantly caused the increase of Malondialdehyde (MDA) (P< 0.05).Treatment with 7,8-DHF preliminarily increased the quantity of MDA controlled with the 6-OHDA group(P<0.05).
6. Treatment with 7,8-DHF preliminarily can significantly cause the increase of Superoxide Dismutase(SOD) activity (P<0.01)
These data demonstrated that 7,8-DHF have neuroprotective effects against the 6-OHDA-induced neurotoxicity in PC 12 cells and their actions might involve inhibiting PC12 cells apoptosis,activation of PI3K/Akt signaling pathways and the self-anti-oxidative stability of 7,8-DHF.These results not only provide new mechanism for the neuroprotective effects of 7,8-DHF,but also provide experimental evidence for the clinical application of 7,8-DHF for prevention and treatment of Parkinson'disease.
引文
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35刘黎星.雌激素和大豆异黄酮抗帕金森病的作用及其可能机制.泰山医学院学报.2008,29(5)：397-400.
36 Tina LT, Robert LM. Estrogen regμlation of dopamine release in the nucleus ace μMbens:Genomic-and Nongenomic-Mediated effects[J]. Neurochem,1994,62:1750-1756.
37宋雪鹏.葛根素对白发高血压大鼠的降压作用及对其血浆肾素活性的影响.中国药理学报,1998,9(1)：55.
38 Cassidy A, O'Reilly E J, Kay C, Sampson L, Franz M, Forman JP, Curhan G, Rimm EB. Habitual intake of flavonoid subclasses and incident hypertension in adμ Its. Am J Clin Nutr.2011,93(2):338-347.
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