Abstract
Background: BDNF regulates neural plasticity, synaptogenesis, neurogenesis, and cell survival. Clinical and experimental data suggests of participation of brain-derived neurotrophic factor (BDNF) in the pathogenesis of depressive states. It has been shown that low levels of BDNF in the CNS lead to damage in brain structures and development of depression. The application of antidepressants or BDNF-introduction corrects these conditions. However, the therapeutic use of BDNF is limited to a number of negative factors. In the Research Zakusov Institute of Pharmacology a low molecular weight BDNF mimetic GSB-106, a substituted dimeric dipeptide, hexamethylenediamide-bis (N-monosuccinyl-L-seryl-L-lysine) was constructed and synthesized. GSB-106 is shown to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK / ERK and PI3K / AKT.
Methods: Porsolt forced swimming test, tail suspension test, learned helplessness, social defeated stress, model of Alzheimer's disease (ICV injection of Amyloid beta), Morris water maze, elevated plus-maze, open field.
Results: In the rodent studies (white outbred male mice and rats) it has been established that GSB-106 at a wide range of doses (0.1-5 mg / kg) showed an antidepressant effect in various models of a depressive state (Porsolt test, suspension of mice by tail, the learned helplessness, the stress of social defeat). The effect of the compound has been observed in various modes of administration (i.p., intragastric), with repeated (4-5 days) and prolonged (14-28 days) administration to animals. In addition to its main antidepressant effect, GSB-106 has shown neuroprotective activity in the Alzheimer's model (ICV injection of Amyloid beta), in which the compound significantly corrects the disturbances in spatial memory in the Morris water maze. Possessing low toxicity, GSB-106 has not revealed any side effects in elevated plus-maze and open field.
Conclusions: The data obtained in this study on the antidepressant activity of the low molecular weight BDNF mimetic GSB-106 confirms the hypothesis that BDNF is involved in the pathogenesis of various forms of depressive states and open the prospect of developing a new antidepressant drug based on the newly synthesized compound.
