Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150001, PR China.
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150001, PR China; Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150001, PR China.
Neuropharmacology. 2019 Dec 1;160:107777. doi: 10.1016/j.neuropharm.2019.107777. Epub 2019 Sep 12.
Oxidative stress plays a critical role in mutant copper/zinc superoxide dismutase 1 (SOD1)-linked amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by selective loss of motor neurons. Thus, an anti-oxidative stress remedy might be a promising means for the treatment of ALS. The aim of the present study is to investigate the neuroprotective effects of γ-oryzanol (Orz) and elucidate its relevant molecular mechanisms in mutant hSOD1-linked Drosophila and cell models of ALS. Orz treatment provided neuroprotection in flies with expression of hSOD1-G85R in motor neurons, as demonstrated by the prolonged survival, improvement of motor deficits, reduced oxidative damage and regulated redox homeostasis when compared with those in controls. Moreover, Orz significantly decreased neuronal apoptosis and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutamate-cysteine ligase catalytic subunit (GCLC) antioxidant pathway via activating Akt in hSOD1-G93A-expressing NSC-34 cells. In addition, our results showed that both in vivo and in vitro, Akt served as an upstream regulator of signal transducers and activators of transcription (Stat) 3 stimulated by Orz, which further increased the level of another anti-oxidative stress factor heat-shock protein 70 (HSP70). Altogether, these findings provide evidence that Orz has potential neuroprotective effects that may be beneficial in the treatment of ALS disease with SOD1 mutations.
氧化应激在突变铜/锌超氧化物歧化酶 1（SOD1）相关的肌萎缩侧索硬化症（ALS）中起着关键作用，这是一种致命的神经退行性疾病，其特征是运动神经元的选择性丧失。因此，抗氧化应激疗法可能是治疗 ALS 的一种有前途的方法。本研究旨在探讨γ-谷维素（Orz）的神经保护作用，并阐明其在突变 hSOD1 相关果蝇和 ALS 细胞模型中的相关分子机制。与对照组相比，Orz 处理可延长 hSOD1-G85R 在运动神经元中表达的果蝇的存活时间，改善运动缺陷，减少氧化损伤并调节氧化还原稳态，从而提供神经保护作用。此外，Orz 通过在表达 hSOD1-G93A 的 NSC-34 细胞中激活 Akt，显著降低神经元凋亡并上调核因子红细胞 2 相关因子 2（Nrf2）/谷胱甘肽半胱氨酸连接酶催化亚基（GCLC）抗氧化途径。此外，我们的结果表明，无论是在体内还是体外，Akt 均作为 Orz 刺激的信号转导子和转录激活子（Stat）3 的上游调节剂，这进一步增加了另一种抗氧化应激因子热休克蛋白 70（HSP70）的水平。总之，这些发现为 Orz 具有潜在的神经保护作用提供了证据，这可能有益于治疗具有 SOD1 突变的 ALS 疾病。
