Institute of Physiologically Active Compounds, Russian Academy of Science, Chernogolovka, Russia.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
CNS Neurosci Ther. 2021 Jul;27(7):765-775. doi: 10.1111/cns.13637. Epub 2021 Mar 23.
To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein.
Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre-symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA-seq was used to compare the spinal cord transcriptomes of wild-type, untreated, and DF402-treated FUS transgenic mice.
DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern.
DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.
评估 DF402（二苯并呋喃类似物）对表达致病性人类 FUS 蛋白截断形式的肌萎缩侧索硬化症（ALS）转基因模型疾病进展的影响。
从 42 天大开始，将 DF402 给予小鼠，监测实验组和对照组动物的发病、疾病持续时间和动物寿命，并在预症状阶段使用 CatWalk 系统评估它们的多项步态参数，然后进行生物信息学分析。使用 RNA-seq 比较野生型、未处理和 DF402 处理的 FUS 转基因小鼠的脊髓转录组。
DF402 可延迟发病并减缓病理进展。我们开发了一种 CatWalk 分析方案，该方案可在 FUS 转基因小鼠的早期预症状阶段检测到步态变化以及 DF402 对其步态的影响。在这一阶段，一小部分基因的表达发生了显著变化，而对于其中 60%的基因，DF402 处理导致其表达模式的恢复。
DF402 可减缓 ALS 小鼠模型的疾病进展，这与先前报道的 Dimebon 及其其他生物类似物的神经保护特性一致。这些结果表明，这些结构可被视为进一步优化的先导化合物，以获得可能用作复杂 ALS 治疗组成部分的新型药物。
