上海中医药大学徐宏喜等研究人员合作发现，人参皂苷Rg1通过激活mTOR信号抑制自噬来减轻小鼠脑缺血/再灌注损伤。该项研究成果于2024年6月27日在线发表在《中国药理学报》杂志上。

研究人员表示，再灌注损伤有别于缺血损伤，当先前缺血的脑组织恢复血流时会发生再灌注损伤，进一步损害神经元和其他细胞，使损伤恶化。目前还缺乏专门减轻脑缺血/再灌注（I/R）损伤的药物和治疗干预措施。人参皂苷Rg1（Rg1）是从人参中分离出来的一种原人参三醇型皂苷，已被发现能保护大脑免受I/R损伤，但其复杂的保护机制仍有待阐明。大量研究表明，自噬在I/R过程中对保护脑组织起着至关重要的作用，并正在成为一种有前途的有效治疗策略。

研究人员探讨了Rg1是否能通过调节自噬在体外和体内保护脑组织免受I/R损伤。研究人员建立了MCAO和OGD/R模型。对SK-N-AS和SH-SY5Y细胞进行OGD，然后用Rg1（4-32 μM）进行再灌注。在手术前3天和手术当天，给MCAO小鼠注射Rg1（30 mg/kg，每天）。Rg1治疗在体外和体内都能明显减轻缺血/再灌注损伤。此外，研究人员还证明了自噬的诱导有助于I/R损伤，而在体外和体内脑I/R损伤模型中，Rg1都能有效抑制自噬。Rg1通过多个步骤抑制自噬，包括阻碍自噬启动、诱导溶酶体功能障碍和抑制酪蛋白酶活性。

研究人员发现，mTOR激活是介导Rg1对自噬抑制作用的关键。用自噬诱导剂和mTOR特异性抑制剂Torin-1治疗可显著逆转Rg1对自噬的影响，降低其在体外和体内对I/R损伤的保护效力。总之，这些研究结果表明，Rg1可通过激活mTOR信号抑制自噬，是一种很有前途的抗脑I/R损伤候选药物。

附：英文原文

Title: Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling

Author: Xi, Zhi-chao, Ren, Han-gui, Ai, Lin, Wang, Yuan, Liu, Meng-fan, Qiu, Yu-fei, Feng, Ji-ling, Fu, Wang, Bi, Qian-qian, Wang, Feng, Xu, Hong-xi

Issue&Volume: 2024-06-27

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 (4–32μM). MCAO mice were injected with Rg1 (30mg·kg1·d1. 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.

DOI: 10.1038/s41401-024-01334-4

Source: https://www.nature.com/articles/s41401-024-01334-4