The BDNF Loop 4 Dipeptide Mimetic Bis(<em>N</em>-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide Is Active in a Depression Model in Mice after Acute Oral Administration

Low-molecular mimetic BDNF GSB-106, which is a substituted dimeric dipeptide, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, was designed and synthesized in the V. V. Zakusov Research Institute of Pharmacology. The dipeptide activates TrkB, PI3K/AKT, and MAPK/ ERK. GSB-106 is being developed as a potential antidepressant. Its antidepressant activity was detected in a number of rodent tests (0.1–1.0 mg/kg, ip; 0.5–5.0 mg/kg, po). In the present study, GSB-106 was shown to completely eliminate the manifestation of anhedonia in the sucrose preference test and to increase disturbed hippocampal synaptogenesis at acute oral administration (0.1 mg/kg) after 10-day social defeat stress in C57Bl/6 mice

Glyproline Pro-Ampakine with Neuroprotective Activity

Previously it was shown that neuropeptide cyclo-L-prolylglycine (CPG) is a positive modulator of AMPA receptors, which increases BDNF level in neuronal cell cultures. The spectrum of CPG’s pharmacological effects corresponds to that of BDNF. Dipeptide N-phenylacetyl-glycyl-L-proline ethyl ester (GZK-111) was designed and synthesized as a linear analog of CPG. The aim of the present work was to reveal the pharmacological profile of GZK-111. Dipeptide GZK-111 was shown to metabolize into CPG in vitro and increased cell survival by 28% at concentrations of 10-7–10-6 M in a Parkinson’s disease cell model. In a model of cerebral ischemia, GZK-111, at a dose of 0.5 mg/kg, i.p., was found to have neuroprotective effects, reducing the cerebral infarct volume by 1.6 times. Similar to CPG, GZK-111, at the range 0.1–1.0 mg/kg, i.p., possessed a stereospecific antiamnesic activity. A significant anxiolytic effect was observed at a dose of 1.5 mg/kg. GZK-111, at the range 0.5–4.0 mg/kg, i.p., demonstrated analgesic activity. GZK-111, at a dose of 10 mg/kg/7 days, i.p., possessed antidepressant-like activity. So, the neuroprotective, nootropic, antihypoxic, anxiolytic, antidepressant-like, and analgesic effects of GZK-111 were revealed. Thus, GZK-111 can be considered as a pharmacologically active pro-ampakine with a BDNF-ergic mechanism of action

Low-Molecular Weight BDNF Mimetic, Dimeric Dipeptide GSB-106, Reverses Depressive Symptoms in Mouse Chronic Social Defeat Stress

A mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, named GSB-106, was designed and synthesized in our scientific group. The compound activated TrkB, MAPK/ERK, PI3K/AKT, and PLCγ in in vitro experiments. In vivo experiments with rodents revealed its antidepressant-like activity in the forced swim and the tail suspension tests at the dose range of 0.1–5.0 mg/kg (i.p., p.o.). However, GSB-106 was not studied in depression models modulating major depression in humans. In the present study, the GSB-106 antidepressant-like activity was revealed in mice at the depression model induced by 28-day social defeat stress with 21-days oral administration (0.1 mg/kg) after stress. At the same time, GSB-106 restored reduced locomotor activity and completely eliminated the anhedonia manifestations. The compound also restored reduced levels of synaptophysin and CREB in the hippocampus. In addition, the Trk receptor antagonist K252A, and the PLC inhibitor U73122, were found to completely block the antidepressant-like activity of GSB-106 in the forced swimming test in mice. Thus, the present results demonstrate the dipeptide BDNF mimetic GSB-106 reversed depressive-like behavior and restored hippocampal neuroplasticity in a rodent depression model. These effects of GSB-106 are probably regulated by TrkB signaling