Protection of Gypenoside XVII against cerebral ischemia/reperfusion injury across the SIRT1-FOXO3A and Hif1a-BNIP3-mediated mitochondrial autophagy

Background: Mitochondrial autophagy maintains mitochondrial function and cellular homeostasis, and plays a critical role in the pathological process of cerebral ischemia/reperfusion injury (CIRI). Whether Gypenoside XVII (GP17) has regulatory effects on mitochondrial autophagy against CIRI remains unclear. The purpose of this study was to investigate the pharmacodynamic effect and mechanism of GP17 on mitochondrial autophagy after CIRI. Methods: A rat model exposed to middle cerebral artery occlusion/reperfusion (MCAO/R) was used to assess the effects of GP17 against CIRI and to explore the underlying mechanisms. The oxygen-glucose deprivation/reoxygenation (OGD/R) cell model was used to verify the effects of ameliorating mitochondria damages and to probe the autophagy pathways of combating neural injuries. Results: The in vivo results shows that GP17 significantly improves mitochondrial metabolic functions and suppresses cerebral ischemia injuries, which might be involved in the autophagy pathway. The further researches reveal that GP17 maintains the moderate activation of autophagy under the ischemia and OGD conditions, producing neuroprotective effects again CIRI, and the regulation of mitochondrial autophagy is associated with a crosstalk between SIRT1-FOXO3A and Hif1a-BNIP3 signaling pathways, which are partially eliminated by special inhibitors AGK-7 and 2-ME. Conclusions: Overall, this work offers new insights for exploring mechanisms by which GP17 protects against CIRI, and highlights the potential that therapy with Notoginseng leaf triterpenes as a novel clinical drug in humans.