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Хорошо известно, что нейротрофины фактор роста нервов (NGF) и мозговой нейротрофический фактор (BDNF) участвуют в процессах обучения и памяти. В НИИ фармакологии имени В. В. Закусова сконструированы и синтезированы димерные дипептидные миметики 1-й (ГК-6) и 4-й (ГК-2) петель NGF, 1-й (ГСБ-214), 2-й (ГТС-201) и 4-й (ГСБ-106) петель BDNF, активирующие in vitro соответственно TrkA- или TrkB-рецепторы. При инкубации в культуре клеток НТ-22 в течение 5 – 180 мин были зарегистрированы различия в активации сигнальных путей PI3K/AKT, MAPK/ERK и PLC-γ1. Целью данной работы было изучение мнемотропной активности оригинальных миметиков NGF и BDNF в тесте распознавания нового объекта у крыс. Дипептиды вводили однократно внутрибрюшинно. Установлено, что ГК-2 (0,5 и 1,0 мг/кг) и ГСБ-214 (0,1 и 1,0 мг/кг), активирующие сигнальные пути PI3K/AKT и PLC-γ1 без влияния на MAPK/ERK, статистически значимо улучшали долговременную память. Соединения ГК-2 и ГСБ-214 представляются перспективными для дальнейшей разработки в качестве средств коррекции нарушений памяти.

Background: A dimeric dipeptide mimetic of the BDNF loop 4, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106), which activates TrkB, PI3K/AKT, MAPK/ERK and PLC-γ1 was created at the V.V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration. Objective: In this work, we studied the GSB-106 effect on the cerebral infarct volume, as well as on neurogenesis and synaptogenesis under experimental ischemic stroke, induced by intravascular occlusion of the middle cerebral artery in rats. Methods: GSB-106 was administered i.p. in a dose of 0.1 mg/kg 24 h after surgery and then once a day, with the end of administration on the day 6 after surgery. On the day 7 brain samples were collected for morphometric and biochemical (Western-blot) analysis. Results: It was established that GSB-106 reduced the brain damage volume by 24%, restores impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and in the striatum and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum. Conclusions: Thus, the dimer dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at clinically relevant time window (24 h) in a model of ischemic stroke presumably due to stimulation of neurogenesis (and/or gliogenesis) and synaptogenesis.

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Background. A dimeric dipeptide mimetic of the brain-derived neurotrophic factor loop 4, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106), which activates TrkB, PI3K/AKT, MAPK/ERK and PLC-γ1 was created at the V. V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration.   Objective. In the present study, we studied the effect of GSB-106 on the brain infarct volume, as well as on neurogenesis and synaptogenesis under conditions of experimental ischemic stroke induced by transient occlusion of the middle cerebral artery in rats, when it was first administered 24 h after ischemia onset.   Methods. Dipeptide GSB-106 was administered i.p. in a dose of 0.1 mg/kg 24 h after surgery and then once a day, with the end of administration on theday 6 after surgery. On the day 7 brain samples were collected for morphometric and biochemical (Western-blot) analysis.   Results. It was established that GSB-106 reduced the brain damage volume by 24%, restores impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and in the striatum and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum.   Conclusions. Thus, the dimeric dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at clinically relevant time window (24 h) in a model of ischemic stroke presumably due to stimulation of neurogenesis (and / or gliogenesis) and synaptogenesis.