Oxidative stress in ALS: Key role in motor neuron injury and therapeutic target

被引:444
作者
Barber, Sian C.
Shaw, Pamela J. [1 ]
机构
[1] Univ Sheffield, Acad Neurol Unit, Sheffield S10 2RX, S Yorkshire, England
基金
英国惠康基金;
关键词
Amyotrophic lateral sclerosis; Antioxidant; Oxidative stress; Reactive oxygen species; Superoxide dismutase; Free radicals; AMYOTROPHIC-LATERAL-SCLEROSIS; CU/ZN-SUPEROXIDE-DISMUTASE; TRANSGENIC MOUSE MODEL; ENDOPLASMIC-RETICULUM STRESS; FRONTOTEMPORAL LOBAR DEGENERATION; ELEMENT SIGNALING PATHWAY; ELECTRON-TRANSPORT CHAIN; FREE-RADICAL SCAVENGER; SPINAL CORD BARRIER; BLOOD-BRAIN-BARRIER;
D O I
10.1016/j.freeradbiomed.2009.11.018
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to Muscle wasting, paralysis, and death, usually within 2-3 years of symptom onset. The Causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS. (C) 2009 Elsevier Inc. All rights reserved
引用
收藏
页码:629 / 641
页数:13
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