Induction of PC12 cell differentiation by flavonoids is dependent upon extracellular signal-regulated kinase activation

J Neurochem. 2004 Sep;90(5):1144-55. doi: 10.1111/j.1471-4159.2004.02563.x.


Many of the physiological benefits attributed to flavonoids are thought to stem from their potent antioxidant and free radical scavenging properties. Recently, it was shown that flavonoids protect nerve cells from oxidative stress by multiple mechanisms, only one of which is directly related to their antioxidant activity, suggesting that specific flavonoids may have other properties that could make them useful in the treatment of conditions that lead to nerve cell death. In particular, it was asked if any flavonoid could mimic neurotrophic proteins. To examine this possibility, we looked at the ability of flavonoids to induce nerve cell differentiation using PC12 cells. PC12 cells were treated with a variety of flavonoids to determine if there was a correlation between their neuroprotective activity and their neurite outgrowth-promoting activity. In addition, the signaling pathways required for flavonoid-induced differentiation were examined. We found that only a small subset of the flavonoids that were neuroprotective could induce neurite outgrowth by an extracellular signal-regulated kinase-dependent process. There was a strong correlation between the concentrations of the flavonoids that were neuroprotective and the concentrations that induced differentiation. These results suggest that the consumption of specific flavonoids could have further beneficial effects on nerve cells following injury, in pathological conditions or in normal aging.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Ascorbic Acid / pharmacology
  • Blotting, Western / methods
  • Cell Differentiation / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology*
  • Flavonols
  • Free Radical Scavengers / pharmacology
  • GTP Phosphohydrolases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / physiology
  • Nerve Growth Factor / pharmacology
  • PC12 Cells
  • Phosphorylation / drug effects
  • Rats
  • Time Factors
  • ras Proteins / metabolism


  • Enzyme Inhibitors
  • Flavonoids
  • Flavonols
  • Free Radical Scavengers
  • Nerve Growth Factor
  • Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • ras Proteins
  • fisetin
  • Ascorbic Acid
  • Acetylcysteine