TY - JOUR
T1 - Pro-neurogenic, Memory-Enhancing and Anti-stress Effects of DF302, a Novel Fluorine Gamma-Carboline Derivative with Multi-target Mechanism of Action
AU - Strekalova, Tatyana
AU - Bahzenova, Nataliia
AU - Trofimov, Alexander
AU - Schmitt-Bohrer, Angelika G.
AU - Markova, Nataliia
AU - Grigoriev, Vladimir
AU - Zamoyski, Vladimir
AU - Serkova, Tatiana
AU - Redkozubova, Olga
AU - Vinogradova, Daria
AU - Umriukhin, Alexei
AU - Fisenko, Vladimir
AU - Lillesaar, Christina
AU - Shevtsova, Elena
AU - Sokolov, Vladimir
AU - Aksinenko, Alexey
AU - Lesch, Klaus-Peter
AU - Bachurin, Sergey
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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 5HT6 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.
AB - 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 5HT6 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.
KW - Alzheimer's disease
KW - Multi-target mechanisms
KW - Hippocampal plasticity
KW - AMPA receptor
KW - 5-HT6 receptor
KW - Stress and depression
KW - Aggression
KW - STRESS-INDUCED ANHEDONIA
KW - ALZHEIMERS-DISEASE
KW - MULTIFACTORIAL NATURE
KW - TRANSGENIC MICE
KW - RECEPTOR ANTAGONISTS
KW - NEURITE OUTGROWTH
KW - CORTICAL-NEURONS
KW - MOUSE MODEL
KW - DIMEBON
KW - DEPRESSION
U2 - 10.1007/s12035-017-0745-6
DO - 10.1007/s12035-017-0745-6
M3 - Article
C2 - 28856531
SN - 0893-7648
VL - 55
SP - 335
EP - 349
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 1
ER -