Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
Hum Mol Genet. 2010 Jun 1;19(11):2144-53. doi: 10.1093/hmg/ddq093. Epub 2010 Feb 27.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a polyglutamine expansion in huntingtin. There are no treatments that are known to slow the neurodegeneration caused by this mutation. Mutant huntingtin causes disease via a toxic gain-of-function mechanism and has the propensity to aggregate and form intraneuronal inclusions. One therapeutic approach for HD is to enhance the degradation of the mutant protein. We have shown that this can be achieved by upregulating autophagy, using the drug rapamycin. In order to find safer ways of inducing autophagy for clinical purposes, we previously screened United States Food and Drug Administration-approved drugs for their autophagy-stimulating potential. This screen suggested that rilmenidine, a well tolerated, safe, centrally acting anti-hypertensive drug, could induce autophagy in cell culture via a pathway that was independent of the mammalian target of rapamycin. Here we have shown that rilmenidine induces autophagy in mice and in primary neuronal culture. Rilmenidine administration attenuated the signs of disease in a HD mouse model and reduced levels of the mutant huntingtin fragment. As rilmenidine has a long safety record and is designed for chronic use, our data suggests that it should be considered for the treatment of HD and related conditions.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，由亨廷顿蛋白中的多聚谷氨酰胺扩展引起。目前尚无已知的治疗方法可以减缓这种突变引起的神经退行性变。突变型亨廷顿蛋白通过毒性获得性功能机制引起疾病，并且具有聚集和形成细胞内包涵体的倾向。HD 的一种治疗方法是增强突变蛋白的降解。我们已经表明，通过上调自噬，可以实现这一点，使用药物雷帕霉素。为了寻找更安全的方法来诱导自噬用于临床目的，我们之前筛选了美国食品和药物管理局批准的药物，以评估它们的自噬刺激潜力。该筛选表明，利美尼定是一种耐受性好、安全、中枢作用的抗高血压药物，可通过独立于雷帕霉素的哺乳动物靶标的途径在细胞培养中诱导自噬。在这里，我们已经表明利美尼定在小鼠和原代神经元培养物中诱导自噬。利美尼定给药可减轻 HD 小鼠模型中的疾病症状，并降低突变型亨廷顿蛋白片段的水平。由于利美尼定具有长期的安全性记录，并且设计用于慢性使用，我们的数据表明它应该被考虑用于治疗 HD 和相关疾病。
