Cunha-Oliveira Teresa, Montezinho Liliana, Mendes Catarina, Firuzi Omidreza, Saso Luciano, Oliveira Paulo J, Silva Filomena S G
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, Cantanhede, Portugal.
Center for Investigation Vasco da Gama (CIVG), Escola Universitária Vasco da Gama, Coimbra, Portugal.
Oxid Med Cell Longev. 2020 Nov 15;2020:5021694. doi: 10.1155/2020/5021694. eCollection 2020.
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.
肌萎缩侧索硬化症（ALS），也被称为卢伽雷氏病或夏科氏病，是一种致命的神经退行性疾病，它会影响运动神经元（MNs），并在确诊后的2至5年内导致死亡，目前尚无任何有效的治疗方法。尽管导致ALS的病理机制仍然不明，但大量证据表明，与抗氧化防御效率低下相关的活性氧（ROS）过度产生是ALS的一个重要病理特征。大量证据表明，氧化应激（OS）与MNs的丧失和线粒体功能障碍有关，对ALS中的神经退行性变起决定性作用。尽管调节OS是保护MNs免于退化的一种有前景的方法，但在动物模型中具有有益作用的几种抗氧化剂在患者中未能显示出任何治疗益处这一事实引发了几个需要分析的问题。我们使用在PubMed上进行文献搜索的特定查询，在此回顾OS相关机制在ALS中的作用，包括线粒体功能改变在神经退行性变中的影响。我们还描述了主要在ALS的临床前和临床试验中进行测试的抗氧化化合物，并描述了它们各自的作用机制。虽然描述ALS中鉴定出的不同突变中的OS机制的主要目的是阐明OS在ALS中的作用，但描述每种抗氧化剂的阳性和阴性结果旨在为新的干预机会铺平道路。总之，尽管抗氧化策略是减缓疾病进展的一种非常有前景的方法，但迫切需要投入精力来表征代表每种患者亚型的OS特征，以便开发个性化疗法，从而了解对不同患者亚型具有有益作用的抗氧化剂的特性。
