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Calycosin-7-<jats:italic>O<\/jats:italic>-<jats:italic>\u03b2<\/jats:italic>-<jats:italic>D<\/jats:italic>-glucoside (CG) is a representative component of isoflavones in <jats:italic>Radix Astragali<\/jats:italic> (RA). Previous studies have shown that CG has potential neuroprotective effects. However, whether CG alleviates neuronal apoptosis through antioxidant stress after ischemia-reperfusion remains unknown. To investigate the positive effects of CG on oxidative stress and apoptosis of neurons, we simulated the ischemia-reperfusion process <jats:italic>in vitro<\/jats:italic> using an immortalized hippocampal neuron cell line (HT22) and oxygen-glucose deprivation\/reperfusion (OGD\/R) model. CG significantly improved cell viability and reduced oxidative stress and neuronal apoptosis. In addition, CG treatment upregulated the expression of SIRT1, FOXO1, PGC-1<jats:italic>\u03b1<\/jats:italic>, and Bcl-2 and downregulated the expression of Bax. In summary, our findings indicate that CG alleviates OGD\/R-induced damage via the SIRT1\/FOXO1\/PGC-1<jats:italic>\u03b1<\/jats:italic> signaling pathway. 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