Deprenyl prevents MPP(+)-induced oxidative damage in PC12 cells by the upregulation of Nrf2-mediated NQO1 expression through the activation of PI3K/Akt and Erk.
Neuroprotection has been the focus of several current efforts to develop a strategy for the treatment of Parkinson's disease (PD). The B-type monoamine oxidase (MAO-B) inhibitor deprenyl (selegiline) is used clinically as a PD therapeutic agent, however, its cytoprotective mechanism has not yet been fully elucidated. In this study, we show that deprenyl upregulates the expression and activity of NAD(P)H: quinone oxidoreductase 1 (NQO1), attenuates the increase in the quinoprotein levels in 1-methyl-4-phenylpyridinium (MPP(+))-treated PC12 cells, and protects PC12 cells from oxidative damage. Deprenyl triggers the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway by increasing the nuclear translocation and DNA-binding activity of Nrf2. Both the antioxidant activity of deprenyl and its effect on NQO1 upregulation were greatly attenuated in Nrf2 siRNA transfected cells. The phosphorylation of extracellular regulating protein kinase (Erk) and Akt can be induced by the administration of 50μM deprenyl in PC12 cells, and the ability of deprenyl to enhance NQO1 expression and Nrf2 nuclear translocation is partly attenuated by the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 and is almost completely attenuated by the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002. The activation of Nrf2/ARE signaling by deprenyl in PC12 cells is independent of MAO-B inhibition. Altogether, our findings indicate that deprenyl protects PC12 cells exposed to MPP(+) resulting from oxidative stress via the Nrf2-mediated upregulation of NQO1 involving both the PI3K/Akt and Erk pathways.
Department of Neurology, Shenzhen Nanshan Hospital, Shenzhen 518052, People's Republic of China.
Haibing
H
Xiao
Feng
F
Lv
Wuping
W
Xu
Linhong
L
Zhang
Ping
P
Jing
Xu
X
Cao
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D012642:Selegiline / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
D000975:Antioxidants; D000978:Antiparkinson Agents; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D012642:Selegiline; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D015655:1-Methyl-4-phenylpyridinium