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.

中文翻译：

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阿魏酸通过ERK1 / 2依赖性Nrf2激活改善了MPP + / MPTP诱导的氧化应激：帕金森病治疗的转化意义。

帕金森氏病（PD）是与氧化应激密切相关的神经退行性疾病。用诱发帕金森氏症的神经毒素MPP + / MPTP处理细胞和小鼠后发生的生化和细胞变化与特发性PD明显相似。以前，我们表明阿魏酸（FA）具有抗氧化特性，并且具有激活核因子E2相关因子2（Nrf2）的能力。本研究检验了FA通过调节Sirtuin 2（SIRT2）和Nrf2途径之间的串扰来减轻MPP + / MPTP诱导的氧化应激的假设。为了验证这一假设，我们使用MPP + / MPTP攻击的SH-SY5Y细胞或经FA处理或未经FA处理的小鼠进行了体外和体内研究。在以MPP +攻击的SH-SY5Y细胞中，FA与α-突触核蛋白平行抑制SIRT2的转录和翻译水平。此外，如活性氧，脂质氢过氧化物，GSH / GSSG比和NAD + / NADH比所示，FA减弱了MPP +诱导的氧化应激。在机制上，FA在转录和翻译水平上强烈上调谷氨酸半胱氨酸连接酶催化亚基和血红素加氧酶-1的表达。有趣的是，FA介导的细胞外信号调节激酶1和2（ERK1 / 2）的激活通过从头合成促进了Nrf2的核积累，这通过使用显性负ERK2进行了验证。出人意料的是，FA激活ERK1 / 2和抑制SIRT2是由独立机制介导的。此外，FA改善了MPTP处理的野生型小鼠和α-突触核蛋白基因敲除小鼠的MPTP处理（25 mg / kg，腹腔注射，每天5天）腹中脑的运动功能障碍和氧化应激，但在Nrf2基因敲除小鼠中没有。总的来说，FA通过ERK1 / 2介导的Nrf2途径的激活发挥抗氧化作用，这些结果可能对PD的治疗具有重要的翻译价值。