Vv Zakusov Institute Of Pharmacology

Moscow, United States

Vv Zakusov Institute Of Pharmacology

Moscow, United States
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Gudasheva T.A.,RAS Institute of Chemistry | Povarnina P.,RAS Institute of Chemistry | Logvinov I.O.,VV Zakusov Institute of Pharmacology | Antipova T.A.,VV Zakusov Institute of Pharmacology | Seredenin S.B.,VV Zakusov Institute of Pharmacology
Drug Design, Development and Therapy | Year: 2016

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. © 2016 Gudasheva et al.


Ostrovskaya R.U.,Vv Zakusov Institute Of Pharmacology | Yagubova S.S.,Vv Zakusov Institute Of Pharmacology | Gudasheva T.A.,Vv Zakusov Institute Of Pharmacology | Seredenin S.B.,Vv Zakusov Institute Of Pharmacology
Acta Naturae | Year: 2017

Based on the comorbidity of diabetes, depression, and dementia and recognizing that a deficiency of the nerve growth factor (NGF) is involved in all of these kinds of pathologies, we studied the effect of the mimetic of dimeric dipeptide NGF loop 4, GK-2, on a model of streptozotocin-induced type 2 diabetes in C57Bl/6 mice. GK-2 [hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine)] was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology. The study revealed the ability of GK-2 to ameliorate hyperglycemia induced by streptozotocine (STZ 100 mg/kg i.p.) in C57Bl/6 mice, to restore learning ability in the Morris Water Maze test, and to overcome depression after both intraperitoneal (0.5 mg/kg) and peroral (5 mg/kg) long-term administration. The presence of the listed properties and their preservation in the case of peroral treatment determines the prospects of research. Taking into account the previous findings on the ability of GK-2 to selectively activate PI3K/Akt, these data suggest that Akt-signaling is sufficient for pancreatic beta cell function. GK-2 has been shown to exhibit pronounced neuroprotective activity. The coexistence of neuroprotective and antidiabetic effects is in agreement with the fundamental concept holding that the function of neurons and pancreatic beta cells is controlled by similar mechanisms. © 2017 Park-media, Ltd.


PubMed | VV Zakusov Institute of Pharmacology
Type: | Journal: Drug design, development and therapy | Year: 2016

Two dimeric dipeptides, 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 (1.310Both 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.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.


Chausheva A.I.,Research Center for Medical Genetics | Nikitina V.A.,Research Center for Medical Genetics | Zhanataev A.K.,Vv Zakusov Institute Of Pharmacology | Durnev A.D.,Vv Zakusov Institute Of Pharmacology | Bochkov N.P.,Research Center for Medical Genetics
Cellular Transplantation and Tissue Engineering | Year: 2011

The levels of DNA-damage and 8-oxiguanine were estimated using the comet assay in multipotent mesenchymal stromal cells (MSC) on different passages. Twenty eight cultures MSC from bone marrow of healthy donors have been analyzed. The level of DNA-damages in MSC, estimated as percent of DNA in comet tail (%DNA in comet tail), didn't change in the process of cultivation (3,9±0,4 % on 3-4 passages and 3,8±0,6 % on 10-12 passages). No significant differences in the content of 8-oxiguanine in the DNA of cells at different stages of cultivation (1,9±0,24 p.u. 3-4 passages and 2,1±0,22 p.u. on 10-12 passages) haven't been revealed. The higher levels of DNA damage and apoptotic comets observed in two cultures of MSC.


PubMed | RAS Institute of Chemistry and Vv Zakusov Institute Of Pharmacology
Type: | Journal: Journal of biomedical science | Year: 2015

This study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), were designed based on the most exposed outside fragments of NGF, namely, the loop 1 and loop 4 -turn sequences, respectively. These dipeptides exhibited neuroprotective activity in vitro at micro-nanomolar concentrations.Studies on the mechanism of action revealed that both compounds elevate the level of tyrosine kinase A (TrkA) receptor phosphorylation and that they each have different postreceptor signaling patterns. GK-6 increases the levels of extracellular signal-regulated kinase (ERK) and AKT kinase phosphorylation, whereas GK-2 only increases the level of AKT phosphorylation. Apart from the neuroprotective activity, GK-6 promoted differentiation in PC12 cells, whereas GK-2 did not. Furthermore, it was established that the neuroprotective activity of GK-2 was completely abolished by a selective inhibitor of phosphatidylinositol 3-kinase (LY294002) but not by a specific inhibitor of mitogen-activated protein kinases MEK1 and MEK2 (PD98059). In vivo experiments demonstrated that GK-2 did not induce hyperalgesia, which is one of the primary adverse effects of NGF. By contrast, GK-6 produced a significant decrease in the pain threshold of rats as determined by the tail flick test.The data obtained suggest that dimeric dipeptide NGF mimetics are promising candidates in the development of pharmacological agents with NGF-like activity that are free of the main side effect of NGF.


Gudasheva T.A.,Vv Zakusov Institute Of Pharmacology | Povarnina P.Y.,Vv Zakusov Institute Of Pharmacology | Antipova T.A.,Vv Zakusov Institute Of Pharmacology | Firsova Y.N.,Vv Zakusov Institute Of Pharmacology | And 2 more authors.
Journal of Biomedical Science | Year: 2015

Background: This study aimed at developing nerve growth factor (NGF) mimetics that selectively activate specific biological signals and, as a result, lack the side effects of the full-length protein. Two dimeric dipeptides, bis-(N-aminocaproyl-glycyl-L-lysine) hexamethylenediamide (GK-6) and bis(N-succinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2), were designed based on the most exposed outside fragments of NGF, namely, the loop 1 and loop 4 β-turn sequences, respectively. These dipeptides exhibited neuroprotective activity in vitro at micro-nanomolar concentrations. Results: Studies on the mechanism of action revealed that both compounds elevate the level of tyrosine kinase A (TrkA) receptor phosphorylation and that they each have different postreceptor signaling patterns. GK-6 increases the levels of extracellular signal-regulated kinase (ERK) and AKT kinase phosphorylation, whereas GK-2 only increases the level of AKT phosphorylation. Apart from the neuroprotective activity, GK-6 promoted differentiation in PC12 cells, whereas GK-2 did not. Furthermore, it was established that the neuroprotective activity of GK-2 was completely abolished by a selective inhibitor of phosphatidylinositol 3-kinase (LY294002) but not by a specific inhibitor of mitogen-activated protein kinases MEK1 and MEK2 (PD98059). In vivo experiments demonstrated that GK-2 did not induce hyperalgesia, which is one of the primary adverse effects of NGF. By contrast, GK-6 produced a significant decrease in the pain threshold of rats as determined by the tail flick test. Conclusion: The data obtained suggest that dimeric dipeptide NGF mimetics are promising candidates in the development of pharmacological agents with NGF-like activity that are free of the main side effect of NGF. © 2015 Gudasheva et al.

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