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

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/reper-fusion (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.