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 50 μM 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.

► We investigated deprenyl prevent MPP+-induced cytotoxicity in PC12 cells.
► Deprenyl increases NOQ1 expression by triggering Nrf2 nuclear translocation.
► PI3K/Akt and Erk signals were involved in Nrf2 translocation induced by deprenyl.
► Nrf2-mediated cytoprotective effect of deprenyl does not involve inhibition of MAO-B.