Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention.
Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention.
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DOI：
10.1155/2020/5021694
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发表时间：
2020
影响因子：
--
通讯作者：
Silva FSG
中科院分区：
文献类型：
--
作者：
Cunha-Oliveira T;Montezinho L;Mendes C;Firuzi O;Saso L;Oliveira PJ;Silva FSG
肌萎缩性侧索硬化症（ALS），也被称为Lou Gehrig's病或Charcot病，是一种致命的神经退行性疾病，影响运动神经元（MNs），在诊断后2-5年内导致死亡，没有任何有效的治疗方法。尽管导致ALS的病理机制尚不清楚，但大量证据表明，与抗氧化防御效率低下相关的活性氧（ROS）过量产生是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，并对ALS的神经退行性变起决定性作用。虽然调节OS是一种很有希望的保护MNs免于退化的方法，但在动物模型中具有有益作用的几种抗氧化剂未能在患者中显示出任何治疗益处，这一事实提出了几个应该分析的问题。通过对PubMed文献的特定查询，我们回顾了os相关机制在ALS中的作用，包括线粒体功能改变与神经退行性变的影响。我们还描述了在ALS的临床前和临床试验中主要测试的抗氧化化合物，并描述了它们各自的作用机制。虽然描述肌萎缩侧索硬化症中不同突变中OS机制的主要目的是阐明OS在肌萎缩侧索硬化症中的作用，但描述每种抗氧化剂的阳性和阴性结果的目的是为新的干预机会铺平道路。总之，尽管抗氧化剂策略是一种非常有前途的减缓疾病进展的方法，但为了开发个性化的治疗方法，了解对不同亚型患者有益的抗氧化剂的特征，最需要的是投资于代表每种亚型患者的OS概况的特征。
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.
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影响因子：
11.2
作者：
Ascherio, A;Weisskopf, MG;Thun, MJ
通讯作者：
Thun, MJ
影响因子：
4.2
作者：
Babu, G. Nagesh;Kumar, Alok;Misra, U. K.
通讯作者：
Misra, U. K.
影响因子：
4.2
作者：
Abramova, NA;Cassarino, DS;Bennett, JP
通讯作者：
Bennett, JP
影响因子：
2.5
作者：
ABE, K;PAN, LH;ITOYAMA, Y
通讯作者：
ITOYAMA, Y
影响因子：
11.2
作者：
Beal, MF;Ferrante, RJ;Brown, RH
通讯作者：
Brown, RH