Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death

Free Radic Biol Med. 2010 Sep 1;49(5):800-13. doi: 10.1016/j.freeradbiomed.2010.06.002. Epub 2010 Jun 8.


Oxidative stress can induce cytotoxicity in neurons, which plays an important role in the etiology of neuronal damage and degeneration. This study sought to determine the cellular and biochemical mechanisms underlying resveratrol's protective effect against oxidative neuronal death. Cultured HT22 cells, an immortalized mouse hippocampal neuronal cell line, were used as an in vitro model, and oxidative stress and neurotoxicity were induced in these neuronal cells by exposure to high concentrations of glutamate. Resveratrol strongly protected HT22 cells from glutamate-induced oxidative cell death. Resveratrol's neuroprotective effect was independent of its direct radical scavenging property, but instead was dependent on its ability to selectively induce the expression of mitochondrial superoxide dismutase (SOD2) and, subsequently, reduce mitochondrial oxidative stress and damage. The induction of mitochondrial SOD2 by resveratrol was mediated through the activation of the PI3K/Akt and GSK-3beta/beta-catenin signaling pathways. Taken together, the results of this study show that up-regulation of mitochondrial SOD2 by resveratrol represents an important mechanism for its protection of neuronal cells against oxidative cytotoxicity resulting from mitochondrial oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Cell Death / drug effects
  • Cell Line
  • Cytoprotection / drug effects*
  • Drug Evaluation, Preclinical
  • Glutamic Acid / toxicity
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Mice
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / physiology
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects*
  • Oxidative Stress / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Resveratrol
  • Signal Transduction / drug effects
  • Stilbenes / pharmacology*
  • Superoxide Dismutase / metabolism


  • Antioxidants
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Stilbenes
  • Glutamic Acid
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Phosphatidylinositol 3-Kinases
  • Resveratrol