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

Brain Res. 2016 Jul 15:1643:70-9. doi: 10.1016/j.brainres.2016.04.048. Epub 2016 Apr 21.


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) and

Nad(p)h: quinone 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.

Keywords: Glutamate; Neuroprotection; Nuclear factor erythroid 2 (NF-E2)-related factor 2 signaling; Oxidative stress; Pterostilbene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Glutamic Acid / toxicity
  • Glutathione / metabolism
  • Heme Oxygenase-1 / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology*
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Stilbenes / pharmacology*
  • Superoxide Dismutase / metabolism


  • NF-E2-Related Factor 2
  • Neuroprotective Agents
  • Nfe2l2 protein, mouse
  • Reactive Oxygen Species
  • Stilbenes
  • pterostilbene
  • Glutamic Acid
  • Heme Oxygenase-1
  • Superoxide Dismutase
  • NAD(P)H Dehydrogenase (Quinone)
  • Glutathione