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.
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29 April 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41401-024-01272-1
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81603315, 81730096, 81603316, 81503275, 81730093, 81873026, U1402221), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-004), the State Key Laboratory Fund Open Project (GTZK201610), the China Postdoctoral Science 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), and the Hunan Chinese Herbal Medicine and standardization functions Engineering Research Center (BG201701).
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N.-h.C. designed research; S.-f.C. and Z.Z. performed the cell experiments and Nrf2-related determination; Xin Zhou, Chen Chen, and Dan-dan Liu prepared the animal models; W.-B.H. guided the animal experiments; P.L., Z.-z.W. and Q.-d.A. determined ROS and 8-OHDG in brain slide; S.-f.C., H.-f.G., H.-S.S. and Z.-P.F. wrote the paper.
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Chu, Sf., Zhang, Z., Zhou, X. et al. Ginsenoside Rg1 protects against ischemic/reperfusion-induced neuronal injury through miR-144/Nrf2/ARE pathway. Acta Pharmacol Sin 40, 13–25 (2019). https://doi.org/10.1038/s41401-018-0154-z
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DOI: https://doi.org/10.1038/s41401-018-0154-z
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