Antidepressant-Like Activity of Dimeric Dipeptide Mimetics of Different BDNF Hairpin Loops is Determined by the Activation Pattern of TrkB Receptor Signaling Pathways
Tatyana Alexandrovna Gudasheva*, Polina Povarnina, Anna Vadimovna Tallerova, Sergey Borisovich Seredenin
Background: A growing number of evidence suggest that brain derived neurotrophic factor (BDNF) and signaling at its receptor, TrkB, are involved in the pathogenesis of depression. Earlier, we created dimeric dipeptides on the basis of the beta-turns of BDNF loops 1, 2 and 4 respectively bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide (GSB-214), bis-(N-hexanoyl-L-seryl-L-lysine) hexamethylenediamide (GTS-201) and bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106). All these dipeptides were shown to elevate the TrkB phosphorylation level while having different post-receptor signaling patterns. GSB-106 increased the levels of ERK and AKT kinase phosphorylation, whereas GTS-201 only increased the level of ERK phosphorylation and GSB-214 only increased the level of AKT phosphorylation. All dipeptides have demonstrated neuroprotective activity in vitro. An interesting observation was that GSB-106 exhibited significant antidepressant activity in the forced swimming test in mice, while GTS-201 and GSB-214 did not. These data suggests that the activation of both MAPK/ERK and PI3K/ AKT pathways are essential for the manifestation of antidepressant-like activity by BDNF mimetics. To test this assumption we studied the antidepressant-like activity of GSB-106, GSB-214 and GTS-201 in the social defeat model of depression in mice.
Methods: C57BL/6 mice were exposed to 10 days of social defeat stress. Dipeptides GSB-106, GSB-214 and GTS-201 were administered intraperitoneally (ip) immediately after the each stress exposure session. In twenty-four hours since the last injections of the drugs, the forced swim test was conducted.
Results: Among the studied dipeptide BDNF mimetics only GSB-106 statistically significantly attenuated the increase of immobility time in forced swimming test in stressed mice compared with untreated control. Conclusions: The antidepressant-like activity of the studied dipeptide BDNF mimetics is dependent on activation of both PI3K/AKT and MAPK/ ERK signaling cascades, whereas selective activation of PI3K/AKT or MAPK/ERK pathway does not produce antidepressant effects.