A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice.

Abstract

AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Kirill Chaprov, Alexander Rezvykh, Sergei Funikov, Tamara A Ivanova, Ekaterina A Lysikova, Alexei V Deykin, Michail S Kukharsky, Alexey Yu Aksinenko, Sergey O Bachurin, Natalia Ninkina, Vladimir L Buchman
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 27 Issue 7 Pg. 765-775 (07 2021) ISSN: 1755-5949 [Electronic] England
• PMID: 33754495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Chemical References

• FUS protein, human
• Indoles
• RNA-Binding Protein FUS
• latrepirdine

Topics

• Amyotrophic Lateral Sclerosis (drug therapy, genetics, physiopathology)
• Animals
• Disease Progression
• Gait (drug effects, physiology)
• Humans
• Indoles (administration & dosage, chemistry)
• Mice
• Mice, Transgenic
• RNA-Binding Protein FUS (genetics)