Antioxidant effect of erythropoietin on 1-methyl-4-phenylpyridinium-induced neurotoxicity in PC12 cells

Eur J Pharmacol. 2007 Jun 14;564(1-3):47-56. doi: 10.1016/j.ejphar.2007.02.020. Epub 2007 Feb 17.


The neuroprotective effects of erythropoietin on 1-methyl-4-phenylpyridinium (MPP(+))-induced oxidative stress and apoptosis in cultured PC12 cells as well as the underlying mechanism were investigated. Treatment of PC12 cells with MPP(+) caused the loss of cell viability, which was associated with the elevation in apoptotic rate, the formation of reactive oxygen species and the disruption of mitochondrial transmembrane potential. It was also shown that MPP(+) significantly induced upregulation of Bax/Bcl-2 ratio and activation of caspase-3. In contrast, erythropoietin reversed these phenotypes and had its maximum protective effect at 1 U/ml. The effect of erythropoietin was mediated by the phosphatidylinositol 3-kinase (PI3K) signaling pathway since erythropoietin failed to rescue cells from MPP(+) insult in the presence of the PI3K inhibitor, LY 294002. In addition, the downstream effector of PI3K, Akt, was activated by erythropoietin, and Akt activation was inhibited by LY 294002. Furthermore, the effect of erythropoietin on reactive oxygen species levels was also blocked by LY 294002. These results show that erythropoietin may provide a useful therapeutic strategy for the treatment of oxidative stress-induced neurodegenerative diseases such as Parkinson disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Antioxidants / pharmacology*
  • Apoptosis / drug effects
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Erythropoietin / pharmacology*
  • Flow Cytometry
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Neuroprotective Agents / pharmacology*
  • Neurotoxicity Syndromes / drug therapy*
  • Oxidative Stress / drug effects*
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins
  • Signal Transduction
  • Up-Regulation
  • bcl-2-Associated X Protein / drug effects
  • bcl-2-Associated X Protein / metabolism


  • Antioxidants
  • Neuroprotective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Recombinant Proteins
  • bcl-2-Associated X Protein
  • Erythropoietin
  • Phosphatidylinositol 3-Kinases
  • Caspase 3
  • 1-Methyl-4-phenylpyridinium