Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, 28006 Madrid, Spain.
Department of Biotechnology, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural (ETSIAMN), Universitat Politécnica de València, 46022 Valencia, Spain.
ACS Chem Neurosci. 2022 Jan 19;13(2):275-287. doi: 10.1021/acschemneuro.1c00758. Epub 2021 Dec 28.
Aggregation of mutant huntingtin, because of an expanded polyglutamine track, underlies the cause of neurodegeneration in Huntington disease (HD). However, it remains unclear how some alterations at the cellular level lead to specific structural changes in HD brains. In this context, the neuroprotective effect of the activation of AMP-activated protein kinase (AMPK) appears to be a determinant factor in several neurodegenerative diseases, including HD. In the present work, we describe a series of indole-derived compounds able to activate AMPK at the cellular level. By using animal models of HD (both worms and mice), we demonstrate the in vivo efficacy of one of these compounds (IND1316), confirming that it can reduce the neuropathological symptoms of this disease. Taken together, in vivo results and in silico studies of druggability, allow us to suggest that IND1316 could be considered as a promising new lead compound for the treatment of HD and other central nervous system diseases in which the activation of AMPK results in neuroprotection.
由于扩展的多聚谷氨酰胺链，突变型亨廷顿蛋白的聚集是亨廷顿病（HD）神经退行性变的原因。然而，目前尚不清楚细胞水平的某些改变如何导致 HD 大脑中的特定结构变化。在这种情况下，AMP 激活蛋白激酶（AMPK）的神经保护作用似乎是包括 HD 在内的几种神经退行性疾病的决定因素。在本工作中，我们描述了一系列能够在细胞水平上激活 AMPK 的吲哚衍生化合物。通过使用 HD 的动物模型（包括蠕虫和小鼠），我们证明了其中一种化合物（IND1316）的体内疗效，证实它可以减轻这种疾病的神经病理学症状。综上所述，体内结果和药物可开发性的计算研究使我们能够提出，IND1316 可以被认为是治疗 HD 和其他中枢神经系统疾病的有前途的新先导化合物，在这些疾病中，AMPK 的激活导致神经保护。
