Abstract
Neurotrophins are considered as an attractive target for the development of antidepressants with a novel mechanism of action. Previously, the dimeric dipeptide mimetics of individual loops of nerve growth factor, NGF (GK-6, loop 1; GK-2, loop 4) and brain-derived neurotrophic factor, BDNF (GSB-214, loop 1; GTS-201, loop 2; GSB-106, loop 4) were designed and synthesized. All the mimetics of NGF and BDNF in vitro after a 5–180 min incubation in a HT-22 cell culture were able to phosphorylate the tropomyosin-related kinase A (TrkA) or B (TrkB) receptors, respectively, but had different post-receptor signaling patterns. In the present study, we conduct comparative research of the antidepressant-like activity of these mimetics at acute and subchronic administration in the forced swim test in mice. Only the dipeptide GSB-106 that in vitro activates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and phospholipase C-gamma (PLCγ) post-receptor pathways exhibited antidepressant-like activity (0.1 and 1.0 mg/kg, ip) at acute administration. At the same time, the inhibition of any one of these signaling pathways completely prevented the antidepressant-like effects of GSB-106 in the forced swim test. All the NGF mimetics were inactive after a single injection regardless of post-receptor in vitro signaling patterns. All the investigated dipeptides, except GTS-201, not activating PI3K/AKT in vitro unlike the other compounds, were active at subchronic administration. The data obtained demonstrate that the low-molecular weight BDNF mimetic GSB-106 that activates all three main post-receptor TrkB signaling pathways is the most promising for the development as an antidepressant.
Highlights
Depression is the most common mental disorder: according to WHO estimations, approximately 280 million people in the world suffer from it [1]
We investigated a possible antidepressant-like activity of the dipeptide nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mimetics upon their acute administration
In the previous in vitro studies, we have shown that GSB-106 activates all the three major tropomyosinrelated kinase B (TrkB)-associated signaling pathways—PI3K/AKT, MAPK/ERK, and PLCγ (Table 1) [34]
Summary
Depression is the most common mental disorder: according to WHO estimations, approximately 280 million people in the world suffer from it [1]. Modern monoaminergic antidepressants are effective in about 60% of cases and require long-term use of not less than two-three weeks to achieve a positive effect [2,3]. The development of antidepressants with a new action mechanism is essential. Scientific studies associate the depressive disorder’s pathogenesis with impaired neuroplasticity in the hippocampus and the prefrontal cortex [4]. The central role of the brain-derived neurotrophic factor (BDNF) in neuroplasticity maintenance in these structures is well documented [5,6]. The content of BDNF in blood plasma decreases in people suffering from depression and returns to normal levels after an antidepressant
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