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In the present study,neuroblastoma（SH-SY5 Y）cells were used to investigate the mechanisms mediating the potential protective effects of pterostilbene（PTE）against mitochondrial metabolic impairment and oxidative stress induced by hyperglycemia for mimicking the diabetic encephalopathy.High glucose medium（100 mM）decreased cellular viability after 24 h incubation which was evidenced by:（i）reduced mitochondrial complex I and III activities;（ii）reduced mitochondrial cytochrome C;（iii）increased reactive oxygen species（ROS）generation;（iv）decreased mitochondrial membrane potential（ΔΨm）;and（v）increased lactate dehydrogenase（LDH）levels.PTE（2.5,5,and 10 μM for 24 h）was nontoxic and induced the nuclear transition of Nrf2.Pretreatment of PTE（2.5,5,and 10 μM for 2 h）displayed a dose-dependently neuroprotective effect,as indicated by significantly prevented high glucose-induced loss of cellular viability,generation of ROS,reduced mitochondrial complex I and III activities,reduced mitochondrial cytochrome C,decreased ΔΨm,and increased LDH levels.Moreover,the levels of nuclear factor erythroid 2-related factor 2（Nrf2）,heme oxygenase-1（HO-1）and glutathione S-transferase（GST）were elevated after PTE treatment.In addition,the elevation of nuclear Nrf2 by PTE treatment（10 μM for 2 h）was abolished by Nrf2 siRNA.Importantly,Nrf2 siRNA induced the opposite changes in mitochondrial complex I and III activities,mitochondrial cytochrome C,reactive species generation,ΔΨm,and LDH.Overall,the present findings were the first to show that pterostilbene attenuated high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling,displaying protective effects against mitochondrial dysfunction-derived oxidative stress.