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Pro-neurogenic, Memory-Enhancing and Anti-stress Effects of DF302, a Novel Fluorine Gamma-Carboline Derivative with Multi-target Mechanism of Action.
- Source :
-
Molecular neurobiology [Mol Neurobiol] 2018 Jan; Vol. 55 (1), pp. 335-349. - Publication Year :
- 2018
-
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.
- Subjects :
- Animals
Fluorine Compounds metabolism
Indoles administration & dosage
Indoles chemistry
Male
Memory physiology
Mice
Mice, Inbred C57BL
Neurogenesis physiology
Rats
Receptors, Serotonin metabolism
Stress, Psychological metabolism
Stress, Psychological psychology
Carbolines administration & dosage
Drug Delivery Systems methods
Fluorine Compounds administration & dosage
Memory drug effects
Neurogenesis drug effects
Stress, Psychological drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1182
- Volume :
- 55
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 28856531
- Full Text :
- https://doi.org/10.1007/s12035-017-0745-6