20(R)-ginsenoside Rg3 protects against focal cerebral ischemia‒reperfusion injury by suppressing autophagy via PI3K/Akt/mTOR signaling pathway.

Abstract

Objective: This study aimed to investigate the effect of 20(R)-ginsenoside Rg3 on autophagy induced by cerebral ischemia‒reperfusion injury (CIRI) in rats and explore its regulation of the PI3K/Akt signaling pathway.

Methods: Middle cerebral artery occlusion/reperfusion (MCAO/R) in male rats was injected intraperitoneally with 20(R)-ginsenoside Rg3 (5, 10, 20 mg/kg) 12 h before modeling, 2 h after ischemia and 12 h after reperfusion. Neurobehavioral and neuronal morphological changes were detected 24 hours after brain I/R. In vitro, the OGD/R-induced injury model is replicated in PC12 cells and different concentrations of 20(R)-ginsenoside Rg3 are administered to observe its effects on cell viability and autophagy and PI3K/Akt/mTOR-related protein expression.

Results: Our findings suggest that treatment with 20 mg/kg 20(R)-ginsenoside Rg3 significantly attenuated the neuronal injury, as evidenced by a decreased number of damaged neurons, reduced dissolution of Nissl corpuscles, a fewer autophagosomes, and downregulated expression of Beclin1 and LC3-II/I compared with the MCAO/R group. Furthermore, 20(R)-ginsenoside Rg3 treatment significantly upregulated the expression of p62, p-PI3K, p-AKT, and p-mTOR. In vitro, 20(R)-ginsenoside Rg3 significantly improved the survival rate of cells following OGD/R and markedly attenuated the LY294002 and OGD/R-induced upregulation of Beclin1 and LC3 gene expression. Moreover, 20(R)-ginsenoside Rg3 could rescued the LY294002 and OGD/R-induced downregulation of p62, p-PI3K, p-AKT, and p-mTOR expression.

Conclusions: 20(R)-ginsenoside Rg3 attenuates neuronal injury and motor dysfunction following ischemia-reperfusion by inhibiting the activation of autophagy, and its mechanism is related to the upregulation of the PI3K/Akt/mTOR signaling pathway.