Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway

Apoptosis. 2007 Aug;12(8):1365-75. doi: 10.1007/s10495-007-0065-9.


Apoptosis is a contributing cause of dopaminergic neuron loss in Parkinson disease. Recent work has shown that erythropoietin (EPO) offers protection against apoptosis in a wide variety of tissues. We demonstrate that exposure of PC12 cells to 1-methyl-4-phenylpyridinium ion (MPP(+)) with recombinant human EPO, significantly decreased apoptosis as measured by TUNEL and caspase-3 activity when compared to MPP(+) treatment alone. EPO induced sustained phosphorylation of Akt and its substrate, GSK-3beta, reduced caspase-3 activities in PC12 cells. The anti-apoptotic effect of EPO was abrogated by co-treatment with LY294002, the specific blocker of phosphatidylinositol 3-kinase (PI3K). The effects of EPO on GSK-3beta and caspase-3 activities were also blocked by LY294002. LiCl, the inhibitor of GSK-3beta, downregulated the caspase-3 activity and blocked the apoptosis induced by MPP(+). Finally, we determined that EPO transiently activated the ERK signaling pathway, but PD98059, a specific inhibitor of ERK, does not alter the survival effect of EPO in this model system. Thus, these findings indicate that EPO protects against apoptosis in PC12 cells exposed to MPP(+), through the Akt/GSK-3beta/caspase-3 signaling pathway, but the ERK pathway is not involved in the EPO-dependent survival enhancing effect in this model system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity*
  • Animals
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism*
  • Cell Survival / drug effects
  • Cytoprotection / drug effects
  • Dose-Response Relationship, Drug
  • Erythropoietin / pharmacology*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Neurons / drug effects
  • Neuroprotective Agents / pharmacology
  • Oncogene Protein v-akt / metabolism*
  • PC12 Cells
  • Rats
  • Signal Transduction / drug effects


  • Neuroprotective Agents
  • Erythropoietin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Oncogene Protein v-akt
  • Glycogen Synthase Kinase 3
  • Caspase 3
  • 1-Methyl-4-phenylpyridinium