Abstract
Reperfusion injury, which is distinct from ischaemic injury, occurs when blood flow is restored in previously ischaemic brain tissue, further compromising neurons and other cells and worsening the injury. There is currently a lack of pharmaceutical agents and therapeutic interventions that specifically mitigate cerebral ischaemia/reperfusion (I/R) injury. Ginsenoside Rg1 (Rg1), a protopanaxatriol-type saponin isolated from Panax ginseng C. A. Meyer, has been found to protect against cerebral I/R injury, but its intricate protective mechanisms remain to be elucidated. Numerous studies have shown that autophagy plays a crucial role in protecting brain tissue during the I/R process and is emerging as a promising therapeutic strategy for effective treatment. In this study, we investigated whether Rg1 protected against I/R damage in vitro and in vivo by regulating autophagy. Both MCAO and OGD/R models were established. SK-N-AS and SH-SY5Y cells were subjected to OGD followed by reperfusion with Rg1 (4–32 μM). MCAO mice were injected with Rg1 (30 mg·kg−1·d−1. i.p.) for 3 days before and on the day of surgery. Rg1 treatment significantly mitigated ischaemia/reperfusion injury both in vitro and in vivo. Furthermore, we demonstrated that the induction of autophagy contributed to I/R injury, which was effectively inhibited by Rg1 in both in vitro and in vivo models of cerebral I/R injury. Rg1 inhibited autophagy through multiple steps, including impeding autophagy initiation, inducing lysosomal dysfunction and inhibiting cathepsin enzyme activities. We revealed that mTOR activation was pivotal in mediating the inhibitory effect of Rg1 on autophagy. Treatment with Torin-1, an autophagy inducer and mTOR-specific inhibitor, significantly reversed the impact of Rg1 on autophagy, decreasing its protective efficacy against I/R injury both in vitro and in vivo. In conclusion, our results suggest that Rg1 may serve as a promising drug candidate against cerebral I/R injury by inhibiting autophagy through activation of mTOR signalling.
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Change history
10 February 2025
The original online version of this article was revised: "In this article fig. 7G has been updated".
12 February 2025
A Correction to this paper has been published: https://doi.org/10.1038/s41401-025-01502-0
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Acknowledgements
This work was supported by Natural Science Foundation of Shanghai (23ZR1448700), Shanghai Science and Technology Commission: Scientific and Technological Innovation Action Plan Medical Innovation Research Special Project (23Y11906400), Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (PWR12020-03), The Shanghai University of Traditional Chinese Medicine Budget Project (23KFL041).
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ZCX and HGR designed and performed the experiments, and wrote and revised the paper. LA, YW and JLF performed in vitro experiments. HGR performed in vivo experiments. MFL and YFQ reviewed and revised the paper. WF and QQB analyzed the data. FW and HXX designed the study and supervised the manuscript. All authors read and approved the final manuscript.
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The original online version of this article was revised: "In this article fig. 7G has been updated".
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Xi, Zc., Ren, Hg., Ai, L. et al. Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling. Acta Pharmacol Sin 45, 2474–2486 (2024). https://doi.org/10.1038/s41401-024-01334-4
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