Ginsenoside Rgl protects against ischemic/reperfusioninduced neuronal injury through miR-144/Nrf2/ARE pathway  

作　　者：Shi-feng Chu Zhao Zhang Xin Zhou Wen-bin He Chen Chen Piao Luo Dan-dan Liu Qi-di Ai Hai-fan Gong Zhen-zhen Wang Hong-shuo Sun Zhong-ping Feng Nai-hong Chen 

机构地区：[1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica,Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Shanxi Key Laboratory of Chinese Medicine Encephalopathy,Shanxi University of Chinese Medicine,Jinzhong 030619, China [3]Hunan University of Chinese Medicine,Changsha 410208,China [4]Department of Physiology,Faculty of Medicine,University of Toronto,Toronto,ON MSS1A8, Canada

出　　处：《Acta Pharmacologica Sinica》2019年第1期13-25,共13页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China (81603315,81730096,81603316,81503275,81730093,81873026,U1402221);the CAMS Innovation Fund for Medical Sciences (CIFMS)(2016-12M-1-004);the State Key Laboratory Fund Open Project (GTZK201610);the China Postdoctoral Sclence Foundation (2013M540066);the PUMC Graduate Education and Teaching Reform Project (10023201600801);the Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150);the opening Program of Shanxi Key Laboratory of Chinese Medicine Encephalopathy (CME-OP-2017001);the Hunan Chinese Herbal Medicine and standardization functions Engineering Research Center (BG201701).

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 Rgl against I/R-induced neuronal injury.In OGD/R-treated PC12 cells,Rgl (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 Rgl was independent of disassociation with Keapl,but resulted from post-translational regulations.Knockdown of Nrf2 abolished all the protective changes of Rgl in OG-D/R-treated PC12 cells.Furthermore,Rgl 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 Rgl in OGD/R-treated PC12 cells.In tMCAO rats,administration of Rgl (20 mg/kg).significantly alleviated ischemic injury,and activated Nff2/ARE pathway.The protective effects of Rgl were abolished by injecting of AAV-HIF-miR-144-shRNA into the predicted ischemic penumbra.In conclusion,our results demonstrate that Rgl alleviates oxidative,stress after I/R through inhibiting miR-144 activity and subsequently promoting the Nrf2/ARE pathway at the post-translational-level.

关 键 词：stroke GINSENOSIDE Rgl ischemic/reperfusion OXIDATIVE stress Nrf2/ARE miR-144 PC12 cells tMCAO rats 

分 类 号：R[医药卫生]