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

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.

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

“…As this time was already similar to time that WT spent motionless during assessment of the recall of memory extinction, it was not expected to see further reduction of the freezing time for L‐FUS[1‐359] mice during this assessment and indeed this has not been observed. The decreased level of freezing behaviour in response to a fear‐conditioned stimulus can be interpreted as an impairment of long‐term memory formation in transgenic L‐FUS[1‐359] mice; however it could not be excluded that the decreased anxiety showed in other tests affects animal behaviour in this test as well.…”

“…Twenty‐four hours after the training, this mouse was re‐exposed to the same apparatus chamber and the percentage of time spent freezing was measured for 180 seconds, followed by 7 minutes of re‐exploring the box under shock‐free conditions for memory extinction. Twenty‐four hours later, that is, on the third experimental day, the mouse was exposed to the chamber again and the percentage of time spent freezing was re‐measured for 180 seconds …”

“…Twenty-four hours later, that is, on the third experimental day, the mouse was exposed to the chamber again and the percentage of time spent freezing was re-measured for 180 seconds. 17 Resident-intruder test. Each resident mouse was housed individually, bedding material in resident's cages has not been changed for a week before testing.…”

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

“…But one of the main mechanism of its neuroprotective effect seems to be connected with stabilization of functional activity of mitochondria that protects neurons against the developing degenerative processes in brain 110,111 . Further development of potential neuroprotective agents currently proceeds with Dimebon structural analogs or it bioisosteres in different institutions 102,112–115 as the patents on Dimebon itself was expired in 2015.…”

“…Similar proneurogenic properties were found for DF‐302, a fluorinated analogue of the neuroprotector Dimebon (Figure 6), on the predator stress model. It was found that DF‐302 agent has higher inhibitory activity toward MPT than Dimebon; it was also shown to suppress the stress‐induced decrease in neurogenesis and enhance neurogenesis in naïve animals 112 …”