20(R)‐ginsenoside Rg3 attenuates cerebral ischemia–reperfusion injury by mitigating mitochondrial oxidative stress via the Nrf2/HO‐1 signaling pathway

Abstract

AbstractReducing mitochondrial oxidative stress has become an important strategy to prevent neuronal death in ischemic stroke. Previous studies have shown that 20(R)‐ginsenoside Rg3 can significantly improve behavioral abnormalities, reduce infarct size, and decrease the number of apoptotic neurons in cerebral ischemia/reperfusion injury rats. However, it remains unclear whether 20(R)‐ginsenoside Rg3 can inhibit mitochondrial oxidative stress in ischemic stroke and the potential molecular mechanism. In this study, we found that 20(R)‐ginsenoside Rg3 notably inhibited mitochondrial oxidative stress in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and maintained the stability of mitochondrial structure and function. Treatment with 20(R)‐ginsenoside Rg3 also decreased the levels of mitochondrial fission proteins (Drp1 and Fis1) and increased the levels of fusion proteins (Opa1, Mfn1, and Mfn2) in MCAO/R rats. Furthermore, we found that 20(R)‐ginsenoside Rg3 promoted nuclear aggregation of nuclear factor erythroid2‐related factor 2 (Nrf2) but did not affect Kelch‐like ECH‐associated protein‐1 (Keap1), resulting in the downstream expression of antioxidants. In in vitro oxygen‐glucose deprivation/reperfusion stroke models, the results of PC12 cells treated with 20(R)‐ginsenoside Rg3 were consistent with animal experiments. After transfection with Nrf2 short interfering RNA (siRNA), the protective effect of 20(R)‐ginsenoside Rg3 on PC12 cells was reversed. In conclusion, the inhibition of mitochondrial oxidative stress plays a vital position in the anti‐cerebral ischemia‐reperfusion injury of 20(R)‐ginsenoside Rg3, and its neuroprotective mechanism is related to the activation of the nuclear factor erythroid2‐related factor 2/heme oxygenase 1 signaling pathway.