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/
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