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

Chaprov, Kirill, Rezvykh, Alexander, Funikov, Sergei, Ivanova, Tamara, Lysikova, Ekaterina, Deykin, Alexei, Kukharsky, Michail, Aksinenko, Alexey, Bachurin, Sergey, Ninkina, Natalia and Buchman, Vladimir 2021. A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice. CNS Neuroscience and Therapeutics 10.1111/cns.13637

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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.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Biosciences
Publisher: Wiley
ISSN: 1755-5930
Date of First Compliant Deposit: 11 March 2021
Date of Acceptance: 7 March 2021
Last Modified: 29 Mar 2021 10:20
URI: http://orca.cf.ac.uk/id/eprint/139616

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