D'Amico Emanuele, Factor-Litvak Pam, Santella Regina M, Mitsumoto Hiroshi
Eleanor and Lou Gehrig MDA/ALS Research Center, The Neurological Institute of New York, Columbia University Medical Center, New York, NY 10032, USA.
Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY 10032, USA.
Free Radic Biol Med. 2013 Dec;65:509-527. doi: 10.1016/j.freeradbiomed.2013.06.029. Epub 2013 Jun 21.
Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.
散发性肌萎缩侧索硬化症（ALS）是最具毁灭性的神经疾病之一；大多数患者在症状出现后3至4年内死亡。氧化应激是促氧化/抗氧化平衡的紊乱，有利于促氧化状态。ALS的尸检和实验室研究表明，氧化应激在运动神经元变性和星形胶质细胞功能障碍中起主要作用。脑脊液、血浆和尿液中的氧化应激生物标志物升高，表明中枢神经系统外产生了异常氧化应激。我们的综述表明，农用化学品、重金属、服兵役、职业运动、过度体力消耗、慢性头部创伤和某些食物可能与ALS风险有一定关联，其中风险与吸烟之间的关联更强。在细胞水平上，这些因素都与氧化应激的产生有关。实验研究表明，诱导适度氧化应激的多种损伤组合可对运动神经元产生累加性有害影响，这表明现实环境中的多重暴露很重要。随着疾病进展，营养缺乏、恶病质、心理压力和即将发生的呼吸衰竭可能会进一步增加氧化应激。此外，越来越多的证据表明，ALS可能是一种全身性疾病。实验室、病理学和流行病学证据明确支持氧化应激在致病过程中起核心作用这一假说，尤其是在基因易感性个体中。如果我们要改善ALS的治疗，就需要精心设计的生化和基因流行病学研究，并结合多学科研究方法，这将为我们理解ALS的病因、病理生理学和预后提供至关重要的知识。
