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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.

SUBMITTER: Chaprov K

PROVIDER: S-EPMC8193697 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description:Despite intensive studies that improved our understanding of the disease mechanisms and multiple clinical trials, amyotrophic lateral sclerosis (ALS) remains an uncurable disease. Riluzole and Edaravone, two currently approved drugs, provide limited quality-of-life improvements in ALS patients. This emphasises the importance of searching for new drugs and therapeutic approaches that might be used, most probably in combination, for efficient treatment of ALS. A neuroprotective ability of certain gamma-carbolines, including Dimebon/Latrepirdine and its derivates, has been demonstrated in several models of neurodegeneration, suggesting that these compounds have a potential as components of a multiplex disease-modifying therapy of ALS. In this study we showed that a chronic treatment with a novel Dimebon bioisostere, DF402, delays the onset and slows the progression of pathology in the transgenic model of motor neuron disease caused by expression of pathogenic truncated form of human FUS protein. By using CatWalk gait analysis we have revealed parameters of transgenic animal gait that display changes before manifestation of clinical signs of pathology and parameters that are changed at the pre-symptomatic stage in response to DF402 treatment. RNAseq was used to compare the spinal cord transcriptomes of wild type, untreated and DF402-treated FUS transgenic mice. We found that at the early pre-symptomatic stage a limited number of genes significantly change expression in the spinal cord of transgenic mice and demonstrated that for 60% of these genes DF402 treatment causes the reversion of expression towards levels typical for expression of these genes in the spinal cord of wild type animals.

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