Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins.
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.
Nakaso
Kazuhiro
K
Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1, Nishicho, Yonago 683-8504, Japan. kazuhiro@grape.med.tottori-u.ac.jp
Nakamura
Chiharu
C
Sato
Hiromi
H
Imamura
Keiko
K
Takeshima
Takao
T
Nakashima
Kenji
K
D000975:Antioxidants / Q000378:metabolism*; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012642:Selegiline / Q000008:administration & dosage*
D000975:Antioxidants; D000978:Antiparkinson Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D012642:Selegiline; D019869:Phosphatidylinositol 3-Kinases