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...
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doaj-80abee84b0ed4adea711efbec749317e2020-11-24T20:53:32ZengDove Medical PressDrug Design, Development and Therapy1177-88812016-11-01Volume 103545355329823Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in ratsGudasheva TAPovarnina PLogvinov IOAntipova TASeredenin SBTatyana 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 strokehttps://www.dovepress.com/mimetics-of-brain-derived-neurotrophic-factor-loops-1-and-4-are-active-peer-reviewed-article-DDDTbrain-derived neurotrophic factormimeticPI3K/AKTMAPK/ERKischemic stroke |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gudasheva TA Povarnina P Logvinov IO Antipova TA Seredenin SB |
spellingShingle |
Gudasheva TA Povarnina P Logvinov IO Antipova TA Seredenin SB Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats Drug Design, Development and Therapy brain-derived neurotrophic factor mimetic PI3K/AKT MAPK/ERK ischemic stroke |
author_facet |
Gudasheva TA Povarnina P Logvinov IO Antipova TA Seredenin SB |
author_sort |
Gudasheva TA |
title |
Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats |
title_short |
Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats |
title_full |
Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats |
title_fullStr |
Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats |
title_full_unstemmed |
Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats |
title_sort |
mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats |
publisher |
Dove Medical Press |
series |
Drug Design, Development and Therapy |
issn |
1177-8881 |
publishDate |
2016-11-01 |
description |
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 |
topic |
brain-derived neurotrophic factor mimetic PI3K/AKT MAPK/ERK ischemic stroke |
url |
https://www.dovepress.com/mimetics-of-brain-derived-neurotrophic-factor-loops-1-and-4-are-active-peer-reviewed-article-DDDT |
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