Friedreich's Ataxia:: Disease mechanisms, antioxidant and coenzyme Q10 therapy
Friedreich's Ataxia:: Disease mechanisms, antioxidant and coenzyme Q10 therapy
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DOI：
10.1002/biof.5520180219
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发表时间：
2003-01-01
期刊：
影响因子：
6
通讯作者：
Schapira, AHV
中科院分区：
文献类型：
--
作者：
Cooper, JM;Schapira, AHV
线粒体显然在弗里德赖希共济失调的发病机制中起核心作用。最常见的遗传异常导致蛋白质frataxin的缺乏，该蛋白质是靶向细胞的。自这一发现以来的研究表明，线粒体呼吸链功能障碍，线粒体铁积累和氧化损伤是疾病机制的重要组成部分。虽然frataxin的作用尚不清楚，但目前有证据表明它在线粒体铁处理或铁硫中心合成中发挥作用。我们对疾病机制的理解的这些进展使人们能够探索治疗途径，特别是使用已建立的药物，如抗氧化剂和呼吸链功能增强剂。维生素E治疗已被证明对维生素E缺乏性共济失调患者有益，而CoQ（10）治疗对某些与CoQ（10）缺乏相关的共济失调患者有效。涉及用高剂量维生素E和辅酶Q（10）长期治疗的联合疗法共同针对弗里德赖希共济失调的两个主要特征;线粒体呼吸链功能降低和氧化应激增加。这种疗法清楚地表明，FRDA心肌产生的能量迅速而持续地增加，几乎恢复到正常水平。骨骼肌能量产生的改善与心脏的改善平行，但水平较低。虽然这种治疗似乎减缓了某些临床症状的预期进展，但需要进行更大规模的安慰剂对照研究来证实这些观察结果。其他抗氧化剂策略涉及艾地苯醌、硒和N乙酰半胱氨酸的使用，但只有艾地苯醌的使用涉及相对大量患者的结构化试验。艾地苯醌对大多数患者的心脏肥大有明显的影响，尽管迄今为止还没有任何其他显著的益处报道。
Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ(10) therapy was effective in some patients with ataxia associated with CoQ(10) deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q(10) has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.