Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins

Biochem Biophys Res Commun. 2006 Jan 20;339(3):915-22. doi: 10.1016/j.bbrc.2005.11.095. Epub 2005 Nov 28.


Neuroprotection has received considerable attention as a strategy for the treatment of Parkinson's disease (PD). Deprenyl (Selegiline) is a promising candidate for neuroprotection; however, its cytoprotective mechanism has not been fully clarified. Here, we report a novel cytoprotective mechanism of deprenyl involving PI3K and Nrf2-mediated induction of oxidative stress-related proteins. Deprenyl increased the expression of HO-1, PrxI, TrxI, TrxRxI, gammaGCS, and p62/A170 in SH-SY5Y cells. Deprenyl also induced the nuclear accumulation of Nrf2 and increased the binding activity of Nrf2 to the enhancer region of human genomic HO-1. The Nrf2-mediated induction of antioxidative molecules was controlled by PI3K. Indeed, furthermore, neurotrophin receptor TrkB was identified as an upstream signal for PI3K-Nrf2 activation by deprenyl. These results suggest that the cytoprotective effect of deprenyl is, in part, dependent on Nrf2-mediated induction of antioxidative proteins, suggesting that activation of the PI3K-Nrf2 system may be a useful therapeutic strategy for PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism*
  • Antiparkinson Agents / administration & dosage*
  • Cell Line, Tumor
  • Cytoprotection / drug effects*
  • Dose-Response Relationship, Drug
  • Humans
  • NF-E2-Related Factor 2 / metabolism*
  • Neoplasm Proteins / metabolism
  • Neuroblastoma / metabolism*
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Selegiline / administration & dosage*


  • Antioxidants
  • Antiparkinson Agents
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Neoplasm Proteins
  • Selegiline
  • Phosphatidylinositol 3-Kinases