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Mol Neurobiol. 2018 Jan;55(1):335-349. doi: 10.1007/s12035-017-0745-6.

Pro-neurogenic, Memory-Enhancing and Anti-stress Effects of DF302, a Novel Fluorine Gamma-Carboline Derivative with Multi-target Mechanism of Action.

Author information

1
Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, 97080, Margarete-Höppel-Platz 1, Würzburg, Germany.
2
Department of Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6229 ER, Maastricht, The Netherlands.
3
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Trubetskaya st. 8-2, 119991, Moscow, Russia.
4
I.M. Sechenov Moscow State Medical University, Trubetskaya str. 8, 199991, Moscow, Russia.
5
Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Baltiyskaya str. 8, 125315, Moscow, Russia.
6
Department of Medicinal Chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severniy proezd 1, Chernogolovka, 142432, Moscow Region, Russia.
7
Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany.
8
Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Mohovaya str. 11-4, 125009, Moscow, Russia.
9
Department of Physiological Chemistry, Biocenter, Am Hubland, University of Würzburg, 97074, Würzburg, Germany.
10
Department of Medicinal Chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severniy proezd 1, Chernogolovka, 142432, Moscow Region, Russia. bachurin@ipac.ac.ru.

Abstract

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.

KEYWORDS:

5-HT6 receptor; AMPA receptor; Aggression; Alzheimer’s disease; Hippocampal plasticity; Multi-target mechanisms; Stress and depression

PMID:
28856531
DOI:
10.1007/s12035-017-0745-6

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