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Fluorinated gamma‐carboline derivatives delay motor deficits in transgenic mouse model of neuronal proteinopathy
Author(s) -
Ustyugov Aleksey,
Nebogatikov Vladimir,
Vikhareva Ekaterina,
Aksinenko Alexey,
Fedyaeva Lyudmila,
Mazin Pavel,
Buchman Vladimir,
Bachurin Sergey
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.043282
Subject(s) - genetically modified mouse , transgene , pathogenesis , pathological , medicine , disease , neuroscience , pharmacology , biology , pathology , biochemistry , gene
Abstract Background Aggregation of specific proteins is a key molecular event in pathogenesis of neurodegenerative diseases known as proteinopathies. Various products of this pathological aggregation cause neuronal dysfunction and death by different mechanisms. Prevention of protein aggregation at initial stages of this multistep process is seen as an important mechanism of therapeutic intervention into pathogenesis of proteinopathies. Method We used FUS(1‐359) mouse model of proteinopathy that is characterized by the formation of neuronal inclusions similar in ALS patients to determine effects of oral administration of gamma‐carboline fluorinated derivatives. Chronic treatments started at the age of two month prior to first visible symptoms and continued for 60 days or until the first symptoms were registered. Result A statistically significant increase in the mean lifespan was observed in experimental groups treated with tested compounds compared to the non‐treated control transgenic animals. Administration of fluorinated gamma‐carboline derivatives also statistically significantly delayed the debut of clinical symptoms manifestation of the neurodegenerative process in transgenic animals. Moreover, chronic treatments prevented overall weight loss which was a characteristic feature of the undertreated controls. The most effective fluorinated gamma‐carbolines improved the disease duration leading to significant increase in animal lifespan. We used Noldus Catwalk gate analysis system to study effect of compounds on the very first signs of motor dysfunction. We performed multi‐dimension scaling analysis analyzing data from transgenic mice to identify a set of parameters distinguishing between transgenic and wild type mice prior to neurological pathology symptoms become visible. More detailed characterization of the effect of fluorinated gamma‐carboline derivates on animal nervous system at presymptomatic stage is required for better understanding of the mechanism of the drug action. Conclusion Overall, our study suggests that chronic administration gamma‐carbolines significantly prolongs the presymptomatic stage of FUS‐proteinopathy delaying the symptoms and enhancing the lifespan of treated animals. This study was supported by RSF 19‐13‐00378 (synthesis of compounds) and by the Program of Russian Academy of Sciences #18 (biological studies). Animals were provided by the Bioresource Collection of the Centre for Collective Use IPAC RAS (No. 0090‐2017‐0016).