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线粒体靶向抗氧化剂MitoQ在遗传性肌萎缩侧索硬化模型中的神经保护作用

Neuroprotective effects of the mitochondria-targeted antioxidant MitoQ in a model of inherited amyotrophic lateral sclerosis.

作者信息

Miquel Ernesto, Cassina Adriana, Martínez-Palma Laura, Souza José M, Bolatto Carmen, Rodríguez-Bottero Sebastián, Logan Angela, Smith Robin A J, Murphy Michael P, Barbeito Luis, Radi Rafael, Cassina Patricia

机构信息

Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.

Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.

出版信息

Free Radic Biol Med. 2014 May;70:204-13. doi: 10.1016/j.freeradbiomed.2014.02.019. Epub 2014 Feb 26.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron degeneration that ultimately results in progressive paralysis and death. Growing evidence indicates that mitochondrial dysfunction and oxidative stress contribute to motor neuron degeneration in ALS. To further explore the hypothesis that mitochondrial dysfunction and nitroxidative stress contribute to disease pathogenesis at the in vivo level, we assessed whether the mitochondria-targeted antioxidant [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium methane sulfonate (MitoQ) can modify disease progression in the SOD1(G93A) mouse model of ALS. To do this, we administered MitoQ (500 µM) in the drinking water of SOD1(G93A) mice from a time when early symptoms of neurodegeneration become evident at 90 days of age until death. This regime is a clinically plausible scenario and could be more easily translated to patients as this corresponds to initiating treatment of patients after they are first diagnosed with ALS. MitoQ was detected in all tested tissues by liquid chromatography/mass spectrometry after 20 days of administration. MitoQ treatment slowed the decline of mitochondrial function, in both the spinal cord and the quadriceps muscle, as measured by high-resolution respirometry. Importantly, nitroxidative markers and pathological signs in the spinal cord of MitoQ-treated animals were markedly reduced and neuromuscular junctions were recovered associated with a significant increase in hindlimb strength. Finally, MitoQ treatment significantly prolonged the life span of SOD1(G93A) mice. Our results support a role for mitochondrial nitroxidative damage and dysfunction in the pathogenesis of ALS and suggest that mitochondria-targeted antioxidants may be of pharmacological use for ALS treatment.

摘要

肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病,其特征是运动神经元退化,最终导致进行性瘫痪和死亡。越来越多的证据表明,线粒体功能障碍和氧化应激导致了ALS中的运动神经元退化。为了在体内水平进一步探究线粒体功能障碍和氮氧化应激导致疾病发病机制的假说,我们评估了线粒体靶向抗氧化剂[10-(4,5-二甲氧基-2-甲基-3,6-二氧代-1,4-环己二烯-1-基)癸基]三苯基鏻甲磺酸盐(MitoQ)是否能改变ALS的SOD1(G93A)小鼠模型中的疾病进展。为此,我们从90日龄神经退行性变的早期症状变得明显时起,直至死亡,在SOD1(G93A)小鼠的饮用水中给予MitoQ(500μM)。这种给药方案在临床上是可行的,并且更容易转化应用于患者,因为这相当于在患者首次被诊断为ALS后开始治疗。给药20天后,通过液相色谱/质谱法在所有测试组织中检测到了MitoQ。通过高分辨率呼吸测定法测量,MitoQ治疗减缓了脊髓和股四头肌中线粒体功能的下降。重要的是,MitoQ治疗动物脊髓中的氮氧化应激标志物和病理体征明显减少,神经肌肉接头得到恢复,同时后肢力量显著增加。最后,MitoQ治疗显著延长了SOD1(G93A)小鼠的寿命。我们的结果支持线粒体氮氧化损伤和功能障碍在ALS发病机制中的作用,并表明线粒体靶向抗氧化剂可能在ALS治疗中具有药理学用途。

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