人参皂甙Rg1及染料木素对SK-N-SH神经细胞保护作用的机制研究
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摘要
植物雌激素是一类天然产品,具有类雌激素样作用,可清除自由基和抗氧化。人参皂甙Rg1是人参的主要活性成分,染料木素(Genistein)是大豆异黄酮的主要活性成分,二者均为已知的植物雌激素。研究显示Rg1和染料木素具有神经保护作用,但其详细作用机制目前尚不清楚。本研究应用6-羟基多巴(6-hydroxydopamine,6-OHDA)诱导多巴胺能神经母细胞瘤细胞系SK-N-SH细胞损伤,采用MTT、流式细胞仪、激光共聚焦、RT-PCR、免疫印迹及荧光素酶活性检测等多种评价方法,观察Rg1和染料木素对SK-N-SH神经细胞的保护作用及胰岛素样生长因子Ⅰ受体(Insulin-like Growth Factor-ⅠReceptor,IGF-IR)阻断剂JB-1或雌激素受体(EstrogenReceptor,ER)阻断剂ICI182,780的阻断效应。实验结果如下:
1.6-OHDA可剂量依赖式的损伤SK-N-SH细胞(P＜0.01),Rg1和染料木素可对抗6-OHDA的毒性作用(P＜0.05)。
2.6-OHDA可将细胞停留在G_0G_1期,抑制细胞进入S期。Rg1和染料木素可促进细胞从G_0G_1期进入S期,此作用可以被JB-1或ICI182,780所阻断(P＜0.01)。
3.6-OHDA可明显升高Bax/Bcl-2的基因表达(P＜0.01),Rg1和染料木素则可明显降低Bax/Bcl-2之比值。
4.6-OHDA可明显升高Bax的蛋白表达(P＜0.01),降低Bcl-2的蛋白表达(P＜0.05),Rg1和染料木素则可明显逆转上述改变。
5.Rg1和染料木素可部分拮抗6-OHDA对SK-N-SH细胞线粒体膜电位的降低作用(P＜0.01),此作用可以被JB-1或ICI182,780所阻断(P＜0.01)。
6.Rg1和染料木素可明显升高雌激素反应元件(Estrogen Responsive Elements,ERE)及IGF-IR启动子的荧光活性(P＜0.01)。
以上结果表明人参皂甙Rg1及染料木素可明显对抗6-OHDA对SK-N-SH神经细胞的损伤,其机制可能与IGF-IR途径与ER途径的激活及抗凋亡有关。本研究不仅为Rg1及染料木素的神经保护作用提供了进一步的实验依据,而且为传统中药的新用途和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。
Phytoestrogens are plant-derived compounds that structurally or functionally mimic mammalian estrogens. They have been shown to possess a variety of beneficial effects on human health, including antioxidant and free redical scavenging. Ginsenosides Rg1 is the principal active component of ginseng. Genistein is the major components of soy isoflavone. Both of them are known phytoestrogens and have neuroprotective effects on the nervous system, but the detail mechanism is not very clear. Our present study aims at investigating the neuroprotective effects of ginsenoside Rg1 and genistein against the 6-OHDA-induced neurotoxicity in human dopaminergic neuroblastoma SK-N-SH cells and the blocking effects of insulin like growth factor I receptor (IGF-IR) antagonist JB-1 or estrogen receptor (ER) antagonist ICI182,780 by using MTT assay, flowcytometry, RT-PCR, western blot, confocal and dual luciferase assay. Results were as follows:
1. 6-OHDA induced cell death in a dose-dependent manner (P<0.01) . Rg1 and genistein had neuroprotective effects on cell viability against 6-OHDA-induced neurotoxicity in SK-N-SH cells (P<0.05) .
2. 6-OHDA arrested the cells at G_0G_1 phase, prevented S phase entry. Rg1 and genistein pretreatment could reverse the toxic effect of 6-OHDA. These effects could be completely blocked by IGF-IR antagonist JB-1 or ER antagonist ICI182,780
3. 6-OHDA increased the ratio of the mRNA expression of Bax/Bcl-2 (P<0.01). Pretreatment with Rg1 and genistein could reverse the 6-OHDA-induced increase of the ratio of Bax/Bcl-2.
4. 6-OHDA increased the Bax protein expression (P<0.01) and decreased the Bcl-2 protein expression (P<0.05). These effects could be reversed by Rg1 and genistein pretreatment.
5. Rg1 and genistein could partly attenuate 6-OHDA-induced the decrease in mitochondrial membrane potential (P<0.01). These effects could be completely blocked by IGF-IR antagonist JB-1 or ER antagonist ICI182,780 (P<0.01).
6. Rg1 and genistein could increase the activity of estrogen responsive elements (ERE) and IGF-IR promoter (P<0.01).
These data demonstrated that ginsenoside Rg1 and genistein have neuroprotective effects against the 6-OHDA-induced neurotoxicity in SK-N-SH cells and their actions might involve activation of IGF-IR and ER signaling pathway and anti-apoptosis. These results not only provide new mechanism for the neuroprotective effects of Rg1 and gensitein, but also provide experimental evidence for the clinical application of ginsenoside Rg1 and genistein for prevention and treatment of Parkinson's disease.
1.6-OHDA可剂量依赖式的损伤SK-N-SH细胞(P＜0.01),Rg1和染料木素可对抗6-OHDA的毒性作用(P＜0.05)。
2.6-OHDA可将细胞停留在G_0G_1期,抑制细胞进入S期。Rg1和染料木素可促进细胞从G_0G_1期进入S期,此作用可以被JB-1或ICI182,780所阻断(P＜0.01)。
3.6-OHDA可明显升高Bax/Bcl-2的基因表达(P＜0.01),Rg1和染料木素则可明显降低Bax/Bcl-2之比值。
4.6-OHDA可明显升高Bax的蛋白表达(P＜0.01),降低Bcl-2的蛋白表达(P＜0.05),Rg1和染料木素则可明显逆转上述改变。
5.Rg1和染料木素可部分拮抗6-OHDA对SK-N-SH细胞线粒体膜电位的降低作用(P＜0.01),此作用可以被JB-1或ICI182,780所阻断(P＜0.01)。
6.Rg1和染料木素可明显升高雌激素反应元件(Estrogen Responsive Elements,ERE)及IGF-IR启动子的荧光活性(P＜0.01)。
以上结果表明人参皂甙Rg1及染料木素可明显对抗6-OHDA对SK-N-SH神经细胞的损伤,其机制可能与IGF-IR途径与ER途径的激活及抗凋亡有关。本研究不仅为Rg1及染料木素的神经保护作用提供了进一步的实验依据,而且为传统中药的新用途和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。
Phytoestrogens are plant-derived compounds that structurally or functionally mimic mammalian estrogens. They have been shown to possess a variety of beneficial effects on human health, including antioxidant and free redical scavenging. Ginsenosides Rg1 is the principal active component of ginseng. Genistein is the major components of soy isoflavone. Both of them are known phytoestrogens and have neuroprotective effects on the nervous system, but the detail mechanism is not very clear. Our present study aims at investigating the neuroprotective effects of ginsenoside Rg1 and genistein against the 6-OHDA-induced neurotoxicity in human dopaminergic neuroblastoma SK-N-SH cells and the blocking effects of insulin like growth factor I receptor (IGF-IR) antagonist JB-1 or estrogen receptor (ER) antagonist ICI182,780 by using MTT assay, flowcytometry, RT-PCR, western blot, confocal and dual luciferase assay. Results were as follows:
1. 6-OHDA induced cell death in a dose-dependent manner (P<0.01) . Rg1 and genistein had neuroprotective effects on cell viability against 6-OHDA-induced neurotoxicity in SK-N-SH cells (P<0.05) .
2. 6-OHDA arrested the cells at G_0G_1 phase, prevented S phase entry. Rg1 and genistein pretreatment could reverse the toxic effect of 6-OHDA. These effects could be completely blocked by IGF-IR antagonist JB-1 or ER antagonist ICI182,780
3. 6-OHDA increased the ratio of the mRNA expression of Bax/Bcl-2 (P<0.01). Pretreatment with Rg1 and genistein could reverse the 6-OHDA-induced increase of the ratio of Bax/Bcl-2.
4. 6-OHDA increased the Bax protein expression (P<0.01) and decreased the Bcl-2 protein expression (P<0.05). These effects could be reversed by Rg1 and genistein pretreatment.
5. Rg1 and genistein could partly attenuate 6-OHDA-induced the decrease in mitochondrial membrane potential (P<0.01). These effects could be completely blocked by IGF-IR antagonist JB-1 or ER antagonist ICI182,780 (P<0.01).
6. Rg1 and genistein could increase the activity of estrogen responsive elements (ERE) and IGF-IR promoter (P<0.01).
These data demonstrated that ginsenoside Rg1 and genistein have neuroprotective effects against the 6-OHDA-induced neurotoxicity in SK-N-SH cells and their actions might involve activation of IGF-IR and ER signaling pathway and anti-apoptosis. These results not only provide new mechanism for the neuroprotective effects of Rg1 and gensitein, but also provide experimental evidence for the clinical application of ginsenoside Rg1 and genistein for prevention and treatment of Parkinson's disease.
引文
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