Ferulic Acid Ameliorates MPP+/MPTP-Induced Oxidative Stress via ERK1/2-Dependent Nrf2 Activation: Translational Implications for Parkinson Disease Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder closely associated with oxidative stress. The biochemical and cellular alterations that occur after cell and mouse treatment with the parkinsonism-inducing neurotoxin MPP+/MPTP are remarkably similar to those observed in idiopathic PD. Previously, we showed that ferulic acid (FA) has antioxidant properties and the ability to activate nuclear factor E2-related factor 2 (Nrf2). The present study tested the hypothesis that FA attenuates MPP+/MPTP-induced oxidative stress by regulating crosstalk between sirtuin 2 (SIRT2) and Nrf2 pathways. To test this hypothesis, we performed in vitro and in vivo studies using MPP+/MPTP-challenged SH-SY5Y cells or mice treated with or not with FA. FA marginally inhibited SIRT2 in parallel with α-synuclein at levels of transcription and translation in SH-SY5Y cells challenged with MPP+. Moreover, FA attenuated MPP+-induced oxidative stress, as indicated by reactive oxygen species, lipid hydroperoxides, GSH/GSSG ratio, and NAD+/NADH ratio. Mechanistically, FA strongly upregulated the glutamate cysteine ligase catalytic subunit and heme oxygenase-1 expression at the levels of transcription and translation. Interestingly, FA-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation contributed to nuclear accumulation of Nrf2 via de novo synthesis, which was validated by the use of dominant negative ERK2. Surprisingly, activation of the ERK1/2 and inhibition of SIRT2 by FA are mediated by independent mechanisms. Furthermore, FA ameliorated motor deficits and oxidative stress in the ventral midbrain in MPTP-treated (25 mg/kg, i.p., daily for 5 days) wild-type mice and α-synuclein knockout mice, but not in Nrf2 knockout mice. Collectively, FA exerts antioxidant effects through ERK1/2-mediated activation of the Nrf2 pathway, and these results may have important translational value for the treatment of PD.