Astrocytes are a major constituent of the central nervous system (CNS). Astrocytic oxidative stress contributes to the development of Parkinson’s disease (PD). Maintaining production of antioxidant and detoxification of reactive oxygen and nitrogen species (ROS/RNS) in astrocytes is critical to prevent PD. Study has illuminated that ascorbic acid (AA) stimulates dopamine synthesis and expression of tyrosine hydroxylase in human neuroblastoma cells. However, the role and regulatory mechanisms of AA on detoxification of astrocytes are still unclear. The purpose of our study is in-depth study of the regulatory mechanism of AA on detoxification of astrocytes. We found that AA pretreatment decreased the expression of ROS and inducible nitric oxide synthase (iNOS) in MPP⁺-treated astrocytes. In contrast, the expression levels of antioxidative substances—including superoxide dismutase (SOD), glutathione (GSH), and glutamate-cysteine ligase modifier (GCLM) subunit—were upregulated after AA pretreatment in MPP⁺-treated astrocytes. However, inhibition of NF-κB prevented such AA induced increases in antioxidative substances following MPP⁺ treatment in astrocytes, suggesting that AA improved antioxidative function of astrocytes through inhibiting NF-κB-mediated oxidative stress. Furthermore, in vivo studies revealed that AA preadministration also suppressed NF-κB and upregulated the expression levels of antioxidative substances in the midbrain of MPTP-treated mice. Additionally, pretreatment of AA alleviated MPTP-induced PD-like pathology in mice. Taken together, our results demonstrate that preadministration of AA improves the antioxidative function of astrocytes through suppressing NF-κB signaling, following alleviated the pathogenesis of PD which induced by MPTP. Hence, our findings elucidate a novel protective mechanism of AA in astrocytes.

中文翻译：

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抗坏血酸预处理通过抑制 NF-κB 信号传导抑制 MPTP 诱导的星形胶质细胞氧化应激

星形胶质细胞是中枢神经系统 (CNS) 的主要组成部分。星形胶质细胞氧化应激有助于帕金森病 (PD) 的发展。维持星形胶质细胞中抗氧化剂的产生和活性氧和氮物质 (ROS/RNS) 的解毒对于预防 PD 至关重要。研究表明，抗坏血酸 (AA) 可刺激人神经母细胞瘤细胞中多巴胺的合成和酪氨酸羟化酶的表达。然而，AA对星形胶质细胞解毒的作用和调控机制尚不清楚。我们研究的目的是深入研究AA对星形胶质细胞解毒的调控机制。我们发现 AA 预处理降低了 MPP ⁺中 ROS 和诱导型一氧化氮合酶 (iNOS) 的表达-处理过的星形胶质细胞。相比之下，抗氧化物质的表达水平——包括超氧化物歧化酶 (SOD)、谷胱甘肽 (GSH) 和谷氨酸-半胱氨酸连接酶修饰剂 (GCLM) 亚基——在 MPP ⁺处理的星形胶质细胞中经过 AA 预处理后上调。然而，NF-的抑制κ在抗氧化物质以下MPP乙防止这种AA诱导的增加⁺在星形胶质细胞的治疗，这表明AA通过抑制NF-改善星形细胞的抗氧化功能κ B-介导的氧化应激。此外，体内研究表明，AA 预给药也抑制了 NF- κB 并上调 MPTP 处理小鼠中脑中抗氧化物质的表达水平。此外，AA 的预处理减轻了小鼠中 MPTP 诱导的 PD 样病理。总之，我们的结果证明AA的预先给药即通过抑制NF-改善星形胶质细胞的抗氧化功能κ乙信令，下面减轻其诱导MPTP PD的发病机制。因此，我们的研究结果阐明了星形胶质细胞中 AA 的新保护机制。