Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL, 60611, USA.
Department of Chemistry, Northwestern University, Evanston, IL, 60208, USA.
Sci Rep. 2022 Mar 30;12(1):5383. doi: 10.1038/s41598-022-09332-4.
Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients. Here, we describe a novel in vitro platform that takes advantage of an UMN reporter line in which UMNs are genetically labeled with fluorescence and have misfolded SOD1 toxicity. We report that NU-9, an analog of the cyclohexane-1,3-dione family of compounds, improves the health of UMNs with misfolded SOD1 toxicity more effectively than riluzole or edaravone, -the only two FDA-approved ALS drugs to date-. Interestingly, when NU-9 is applied in combination with riluzole or edaravone, there is an additive effect on UMN health, as they extend longer axons and display enhanced branching and arborization, two important characteristics of healthy UMNs in vitro.
尽管肌萎缩侧索硬化症（ALS）是一种上下运动神经元疾病，但迄今为止，临床试验中的化合物都没有经过测试以改善患病的上运动神经元（UMN）的健康状况。迫切需要开发包括 UMN 健康状况作为检测结果的临床前检测方法。由于 ALS 是一种复杂的疾病，因此需要联合治疗策略来解决患者中受到干扰的机制。在这里，我们描述了一种新颖的体外平台，该平台利用了一种 UMN 报告细胞系，其中 UMN 被荧光基因标记，并具有错误折叠的 SOD1 毒性。我们报告说，NU-9 是环己烷-1,3-二酮类化合物的类似物，比利鲁唑或依达拉奉更有效地改善了具有错误折叠 SOD1 毒性的 UMN 的健康状况，依达拉奉是迄今为止唯一两种获得 FDA 批准的 ALS 药物。有趣的是，当 NU-9 与利鲁唑或依达拉奉联合使用时，对 UMN 健康状况具有相加作用，因为它们可以延长轴突并显示出增强的分支和分支化，这是体外健康 UMN 的两个重要特征。
