Репозиторий Университета

Pro-neurogenic, memory-enhancing and anti-stress effects of DF302, a novel fluorine gamma-carboline derivative with multi-target mechanism of action


  • Strekalova T.
  • Bahzenova N.
  • Trofimov A.
  • Schmitt-Böhrer A.
  • Markova N.
  • Grigoriev V.
  • Zamoyski V.
  • Serkova T.
  • Redkozubova O.
  • Vinogradova D.
  • Umriukhin A.
  • Fisenko V.
  • Lillesaar C.
  • Shevtsova E.
  • Sokolov V.
  • Aksinenko A.
  • Lesch K.
  • Bachurin S.
Дата публикации:01.01.2018
Журнал: Molecular Neurobiology
БД: Scopus
Ссылка: Scopus
Индекс цитирования: 9

Аннтотация

© Springer Science+Business Media New York 2016. A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon.


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