Ginsenoside Rg1 protects against ischemic/reperfusion-induced neuronal injury through miR-144/Nrf2/ARE pathway

• 来源期刊: 中国药理学报（英文版）
• 关键词: stroke ginsenoside Rg1 ischemic/reperfusion oxidative stress Nrf2/ARE miR-144 PC12 cells tMCAO rats
• 年，卷（期）: 2019,（1）
• 页码范围: 13-25
• 页数: 13页
• 语种: 英文

摘要

Ginsenoside Rg1 (Rg1),a saponin extracted from Panax ginseng,has been well documented to be effective against ischemic/reperfusion (I/R) neuronal injury.However,the underlying mechanisms remain obscure.In the present study,we investigated the roles of Nrf2 and miR-144 in the protective effects of Rg1 against I/R-induced neuronal injury.In OGD/R-treated PC12 cells,Rg1 (0.01-1 μmol/L) dose-dependently attenuated the cell injury accompanied by prolonging nuclear accumulation of Nrf2,enhancing the transcriptional activity of Nrf2,as well as promoting the expression of ARE-target genes.The activation of the Nrf2/ARE pathway by Rg1 was independent of disassociation with Keap1,but resulted from post-translational regulations.Knockdown of Nrf2 abolished all the protective changes of Rg1 in OGD/R-treated PC12 cells.Furthermore,Rg1 treatment significantly decreased the expression of miR-144,which downregulated Nrf2 production by targeting its 3'-untranlated region after OGD/R.Knockdown of Nrf2 had no effect on the expression of miR-144,suggesting that miR-144 was an upstream regulator of Nrf2.We revealed that there was a direct binding between Nrf2 and miR-144 in PC12 cells.Application of anti-miR-144 occluded the activation of the Nrf2/ARE pathway by Rg1 in OGD/R-treated PC12 cells.In tMCAO rats,administration of Rg1 (20 mg/kg) significantly alleviated ischemic injury,and activated Nrf2/ARE pathway.The protective effects of Rg1 were abolished by injecting of AAV-HIF-miR-144-shRNA into the predicted ischemic penumbra.In conclusion,our results demonstrate that Rg1 alleviates oxidative stress after I/R through inhibiting miR-144 activity and subsequently promoting the Nrf2/ARE pathway at the post-translational level.