Neuroprotective effects of pterostilbene against oxidative stress injury: Involvement of nuclear factor erythroid 2-related factor 2 pathway

Nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) regulates multiple anti-oxidative enzymes and has neuroprotective effects. Pterostilbene (PTE) is a natural anti-oxidant found in blueberries. Its non-metabolized form exhibits high distribution in the brain after dietary administration. In this study, we aimed to explore the potential of PTE in protecting murine hippocampal neuronal HT22 cells against glutamate-induced oxidative stress injury and possible underlying mechanisms. PTE was nontoxic and induced the nuclear translocation of Nrf2 when HT22 cell cultures were incubated with different concentrations of PTE. Further, PTE displayed a dose-dependent neuroprotective effect, as indicated by increased cell viability and a reduction in lactate dehydrogenase (LDH) release after glutamate treatment. Nrf2 siRNA treatment inhibited PTE-induced neuroprotective effects. Moreover, the levels of nuclear Nrf2 and downstream heme oxygenase-1 (HO-1) andquinone oxidoreductase 1 (NQO1) were elevated after PTE treatment. The PTE-induced elevation of nuclear Nrf2, as well as the increases in HO-1 and NQO1 levels, was abolished by Nrf2 siRNA. PTE treatment reduced the production of reactive oxygen species (ROS) and significantly enhanced the activities of the cellular anti-oxidants glutathione (GSH) and superoxide dismutase (SOD), indicating an attenuation of glutamate-induced oxidative stress. These changes in ROS and GSH and SOD activity were reversed by Nrf2 siRNA. Our results indicate that PTE treatment attenuates glutamate-induced oxidative stress injury in neuronal cells via the Nrf2 signaling pathway.