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• W2548660337 abstract "Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats Tatyana A Gudasheva,1 Polina Povarnina,1 Ilya O Logvinov,2 Tatyana A Antipova,2 Sergey B Seredenin3 1Department of Medicinal Chemistry, 2Department of Neuroprotective Pharmacology, 3Department of Pharmacogenetics, VV Zakusov Institute of Pharmacology, Moscow, Russia Background: Two dimeric dipeptides, bis-(N-monosuccinyl-L-seryl-L-lysine)hexamethy­lenediamide (GSB-106) and bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide (GSB-214), were designed based on the brain-derived neurotrophic factor (BDNF) loop 4 and loop 1 β-turn sequences, respectively. Earlier, both of these dipeptides were shown to exhibit neuroprotective activity in vitro (10-5–10-8 M). The present study aimed to investigate the mechanisms of action of these peptides and their neuroprotective activity in an experimental stroke model. Methods: We used western blot and HT-22 hippocampal neuronal cell line to investigate whether these peptides induced phosphorylation of the TrkB receptor and the AKT and ERK kinases. Rat middle cerebral artery occlusion (MCAO) was used as a stroke model. GSB-106 and GSB-214 were administered intraperitoneally (0.1 mg (1.3×10-7 mol)/kg) 4 hours after MCAO and daily for 7 days. The cerebral infarct volumes were measured with 2,3,5-triphenyltetrazolium chloride staining 21 days after MCAO. Results: Both compounds were shown to elevate the TrkB phosphorylation level while having different post-receptor signaling patterns. GSB-106 activated the PI3K/AKT and MAPK/ERK pathways simultaneously, whereas GSB-214 activated the PI3K/AKT only. In experimental stroke, the reduction of cerebral infarct volume by GSB-106 (~66%) was significantly greater than that of GSB-214 (~28% reduction), which could be explained by the fundamental role of the MAPK/ERK pathway in neurogenesis and neuroplasticity. Notably, between these two dipeptides, only GSB-106 exhibited antidepressant activity, as was found previously. Conclusion: The results provided support for the beneficial pharmacological properties of BDNF loop 4 mimetic GSB-106, thereby suggesting a potential role for this dipeptide as a therapeutic agent. Keywords: brain-derived neurotrophic factor, mimetic, PI3K/AKT, MAPK/ERK, ischemic stroke" @default.
• W2548660337 created "2016-11-11" @default.
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• W2548660337 date "2016-11-01" @default.
• W2548660337 modified "2023-10-18" @default.
• W2548660337 title "Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats" @default.
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• W2548660337 doi "https://doi.org/10.2147/dddt.s118768" @default.
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