Curcumin exerts protective effects against hypoxia?reoxygenation injury via the enhancement of apurinic/apyrimidinic endonuclease?1 in SH?SY5Y cells Involvement of the PI3K/AKT pathway

摘要

Curcumin, a polyphenolic compound extracted from the plant Curcuma longa, has been reported to exert neuroprotective effects against cerebral ischemia?reperfusion (I/R) injury. However, the mechanisms underlying these effects remain to be fully elucidated. Emerging evidence indicated that apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional enzyme, participates in neuronal survival against I/R injury. Therefore, the aim of the present study was to investigate whether curcumin?alleviates oxygen?glucose deprivation/reperfusion (OGD/R)?induced SH?SY5Y cell injury, which serves as an in?vitro model of cerebral I/R injury, by regulating APE1. The results revealed that curcumin increased cell viability, decreased LDH activity, reduced apoptosis and caspase?3 activity, downregulated the pro?apoptotic protein Bax expression and upregulated the anti?apoptotic protein Bcl?2 expression in SH?SY5Y cells subjected to OGD/R. Simultaneously, curcumin eliminated the OGD/R?induced decreases in APE1 protein and mRNA expression, as well as 8?hydroxy?2'?deoxyguanosine (8?OHdG) level and AP sites in SH?SY5Y cells. However, APE1 knockdown by siRNA transfection markedly abrogated the protective effects of curcumin against OGD/R?induced cytotoxicity, apoptosis and oxidative stress, as illustrated by the decreases in reactive oxygen species production and NADPH oxidase 2 expression, and the increase in superoxide dismutase activity and glutathione levels in SH?SY5Y cells. Furthermore, curcumin mitigated the OGD/R?induced activation of phosphatidylinositol 3?kinase/protein kinase?B (PI3K/AKT) signaling pathway. Treatment with LY294002, an inhibitor of PI3K/AKT pathway activity, attenuated the protective effects of curcumin on cytotoxicity and apoptosis, and reversed the curcumin?induced upregulation of APE1 protein expression in SH?SY5Y cells subjected to OGD/R. Taken together, these results demonstrated that curcumin protects SH?SY5Y cells against OGD/R injury by inhibiting apoptosis and oxidative stress, and via enhancing the APE1 level and activity, promoting PI3K/AKT pathway activation.