Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

中文翻译：

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肌萎缩性侧索硬化症中的氧化应激：病理生理学和药物干预的机会。

肌萎缩性侧索硬化症（ALS），也称为Lou Gehrig病或Charcot病，是一种致命的神经退行性疾病，会影响运动神经元（MN），并在诊断后的2-5年内导致死亡，而没有任何有效的治疗方法。尽管尚不清楚导致ALS的病理机制，但大量证据表明，与无效的抗氧化剂防御相关的过量活性氧（ROS）产生代表ALS的重要病理特征。大量证据表明，氧化应激（OS）与MN的丢失和线粒体功能障碍有关，对ALS的神经变性起决定性作用。尽管OS的调制代表了一种保护MN免受退化的有前途的方法，几种在动物模型中具有有益作用的抗氧化剂未能显示出对患者的任何治疗作用，这一事实提出了需要分析的几个问题。在PubMed上使用特定查询进行文献检索时，我们在这里回顾了OS相关机制在ALS​​中的作用，包括线粒体功能的改变与神经变性的影响。我们还描述了主要在ALS的临床前和临床试验中测试过的抗氧化剂化合物，还描述了它们各自的作用机理。尽管描述ALS中鉴定的不同突变中的OS机制的主要目的是阐明OS在ALS中的作用，但是对每种抗氧化剂的阳性和阴性结果的描述旨在为新的干预机会铺平道路。