Ginsenoside Rg1 Protects Against β Amyloid-Induced Neurotoxicity Via Activation Of Er And IGF-IR Signaling Pathways

The present study aims at investigating the protective effects of Rgl against the toxicity of P-amyloid peptide 25-35 (Aβ25-35) and the molecular mechanism. In this research, we used P-amyloid peptide to injure PC 12 cell. MTT, real time RT-PCR, flow cytometry, western blot and transient transfection were used to observe the protective effects of Rg1 againstβ-amyloid peptide and the blocking effects of estrogen receptor (ER) antagonist ICI182,780 or insulin-like growth factor I receptor (IGF-IR) antagonist JB-1. Moreover, the P-amyloid peptide was infused into the lateral cerebral ventricle to damage the hippocampal neurons. Morris water maze and RT-PCR were used to observe the ameliorated effects of Rgl on the spatial learning and memory ability and the blocking effects of ICI182,780 or JB-1. Results are as follows:1. Aβ25.35 decreased cell viability of PC12 cells in a dose-dependent manner (P<0.01). Rgl attenuated the toxicity of Aβ25-35 (P<0.05). These effects could be completely blocked by ICI 182,780 or JB-1 (P<0.05), respectively.2. Aβ25-35 significantly decreased the ratio of Bcl-2/Bax (P<0.001), which was reversed by pretreatment with Rg1 (P<0.05).3. Aβ25-35 significantly decreased mitochondrial membrane potential in PC 12 cells (P<0.001). Rgl could significantly reverse the toxic effects of Aβ25-35 (P<0.001). These effects could be completely blocked by ICI182,780 or JB-1 (P<0.001), respectively.4. Rgl could significantly increase the phosphorylation of MEK in a time-dependent pattern (P<0.05).5. Rgl caused the increase of the fluorescence activity of estrogen responsive elements (ERE) promoter (P<0.05).6. Aβ25-35 damaged the spatial learning and memory ability of mouse (P<0.05). Treatment with Rgl significantly attenuated the toxicity of Aβ25-35 (P<0.001), which could be blocked by ICI 182,780 or JB-1 (P<0.001), respectively. 7. Aβ25-35 significantly decreased the gene expression of Bcl-2 (P<0.01) and increased the gene expression of Bax (P<0.01) in the hippocampus of mouse. Treatment with Rgl could significantly reverse the toxicities of Aβ25-35 (P<0.001, P<0.05). The effect of Rgl on the gene expression of Bcl-2 could be completely blocked by ICI182,780 or JB-1 (P<0.01, P<0.001). While the effect of Rgl on the gene expression of Bax could not be blocked by ICI 182,780 or JB-1.These results indicated that ginsenoside Rgl could significantly attenuate the toxicities of Aβ25-35 in PC 12 cells and hippocampal neurons as well as improve the spatial learning and memory ability of the mouse. These functions might be mediated by the activation of ER and IGF-IR signaling pathways. Our study provided powerful theoretical and experimental supports for the clinical development of new drugs for Alzheimer's disease.