Cerebral ischemia/reperfusion injury is a leading cause of neurological deficits, with limited treatment options available. Ginsenoside Rb1 (GRb1), a major bioactive compound of Panax ginseng, has shown neuroprotective potential. This study investigates whether GRb1 exerts its protective effects against cerebral ischemia/reperfusion injury, focusing on its effects in promoting mitophagy as the underlying mechanism. Male C57BL/6J mice underwent middle cerebral artery occlusion for 30 min followed by reperfusion. Mice were divided into four groups: Sham, Vehicle, GRb1-treated, and GRb1 combined with Mdivi-1, a mitophagy inhibitor. GRb1 (20 mg/kg) and Mdivi-1 (40 mg/kg) were administered intraperitoneally at 1 h, 12 h, and 24 h post-ischemia, followed by daily injections. Cognitive function and anxiety-like behavior were assessed using the Morris Water Maze and Open Field Test. Neuroinflammation, mitochondrial function, and connexin 43 phosphorylation were analyzed through immunofluorescence, Western blot, and ELISA. Mitophagy was evaluated by examining key markers, including PINK1, Parkin, Atg5, LC3 II, and p62. GRb1 significantly improved cognitive function and reduced anxiety-like behavior following ischemia/reperfusion injury. GRb1-treated mice exhibited decreased microglial activation and reduced levels of pro-inflammatory cytokines IL-1β and TNF-α while increasing the anti-inflammatory cytokine IL-10. Additionally, GRb1 preserved mitochondrial function by enhancing ATP production, increasing superoxide dismutase activity, and upregulating PGC1α while reducing Drp1 expression. Western blot analysis revealed that GRb1 decreased connexin 43 phosphorylation and enhanced mitophagy, as indicated by increased levels of PINK1, Parkin, Atg5, and LC3 II, with reduced p62 accumulation. Importantly, these protective effects were largely diminished when mitophagy was inhibited by Mdivi-1. GRb1 exerts its neuroprotective effects against cerebral ischemia/reperfusion injury through the activation of mitophagy. Targeting mitophagy may represent a promising therapeutic strategy for ischemic stroke and related neurological disorders.
Chen et al. (2026) studied this question.