Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy.
Department of Life Sciences, College of Health & Life Sciences, Brunel University London, Uxbridge UB8 3PH, UK.
Hum Mol Genet. 2018 Mar 15;27(6):992-1001. doi: 10.1093/hmg/ddy016.
Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for FRDA available, especially for neurological deficits. In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mammalian target of rapamycin (mTOR) pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3 mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity, and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
弗里德赖希共济失调（FRDA）是一种由线粒体蛋白 frataxin 缺乏引起的遗传性隐性疾病。目前尚无有效的 FRDA 治疗方法，特别是针对神经功能缺陷。在这项研究中，我们测试了二氮嗪，一种常用的血管扩张剂，用于治疗急性高血压，在 FRDA 淋巴母细胞系和动物模型中进行了测试。我们首先表明，二氮嗪通过哺乳动物雷帕霉素靶蛋白（mTOR）途径增加 FRDA 淋巴母细胞系中的 frataxin 蛋白水平。然后，我们探讨了二氮嗪在 frataxin 缺乏的转基因 YG8sR 小鼠中的潜在治疗效果，发现长期口服 3mpk/d 二氮嗪是安全的，但疗效存在差异。YG8sR 小鼠在平衡木行走协调能力和足迹步态模式方面有了改善，但总体运动活性降低。此外，它们的 frataxin 表达显著增加，顺乌头酸酶活性提高，小脑和脑组织线粒体提取物中的蛋白质氧化减少。在考虑将这种药物用于 FRDA 临床试验之前，还需要进一步研究。
