Article

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

Authors: Shi-feng Chu1, Zhao Zhang1, Xin Zhou1, Wen-bin He1,2, Chen Chen1, Piao Luo3, Dan-dan Liu1, Qi-di Ai3, Hai-fan Gong4, Zhen-zhen Wang1, Hong-shuo Sun4, Zhong-ping Feng4, Nai-hong Chen1,3
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 M5S 1A8, Canada
DOI: 10.1038/s41401-018-0154-z
Received: 7 March 2018
Accepted: 18 June 2018
Advance online: 27 September 2018

Abstract

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.
Keywords: stroke; ginsenoside; Rg1; ischemic/reperfusion; oxidative stress; Nrf2/ARE; miR-144; PC12 cells; tMCAO rats

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