Forsythiaside A Ameliorates Oxidative Damage Caused by Cerebral Ischemia Through the Nrf2/HO‐1 Signaling Pathway

ABSTRACT Forsythiaside A (FA) has anti‐inflammatory and antioxidant properties. The aim of this study was to explore the antioxidant effects and mechanisms of FA in ischemic stroke (IS). In this work, IS‐related genes were obtained through GEO, GeneCards, TTD, CTD, DrugBank, and MalaCards databases. The targets of the FA were obtained from CTD, TargetNet, Super‐PRED, TCMIO, and SwissTargetPrediction databases. GO analysis and KEGG pathway enrichment analysis were performed, and a protein–protein interaction (PPI) network was constructed to screen for key pathways. For in vivo assays, a middle cerebral artery occlusion and reperfusion (MCAO/R) model was established in rats, and high and low doses of FA were administered. Neurological impairment score, cerebral infarction, cerebral edema, and tissue morphology were evaluated. The content of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected. The expressions of cleaved caspase 3, Bax, and bcl‐2, and Nrf2/HO‐1 pathway‐related proteins were detected by Western blot. For in vitro experiments, an oxygen–glucose deprivation/reperfusion (OGD/R) model was constructed in HT22 cells, and CCK‐8 and LDH release assays were used to evaluate the effect of FA on OGD/R‐induced toxicity of HT22 neurons. The Nrf2 inhibitor ML385 was used for the rescue experiments. Network pharmacology and bioinformatics analysis showed that the role of FA in treating IS was associated with oxidative stress. Topological analysis of the PPI network revealed 11 key genes, which were closely associated with the Nrf2 pathway. FA treatment could significantly reduce cerebral infarction, cerebral edema, neurological function impairment, and neuronal injury of the rats with MCAO/R. FA could also inhibit oxidative stress and neuronal apoptosis, and increase the viability of HT22 cells. In addition, FA promoted the nuclear translocation of Nrf2 and activated the Nrf2/HO‐1 pathway, while ML385 weakened the protective effect of FA on neuronal viability and antioxidant capacity. In conclusion, FA attenuates the oxidative damage induced by IS by activating the Nrf2/HO‐1 signaling pathway, which is a promising natural drug for IS.