Brain-derived neurotrophic factor loop 4 dipeptide mimetic GSB-106 activates TrkB, Erk, and Akt and promotes neuronal survival in vitro

Gudasheva, T. A.; Logvinov, I. O.; Антипова, Т. А.; Seredenin, S. B.

doi:10.1134/s1607672913040121

Cited by 30 publications

(19 citation statements)

References 12 publications

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“…Induction of neurogenesis in the hippocampus and midbrain was a functional consequence of the antidepressant action of recombinant BDNF; the authors attributed its mechanism to the increased BDNF level and to the increased level of activation/phosphorylation of ER K and CRE B in the downstream targets of the BDNF-TrkB signaling pathways [22]. Previously, we found that GSB-106, the mimetic of BDNF, activates TrkB and its ER K and the AKT signaling pathways [23] involved in neuronal survival and this fact could presumably underly its antidepressant effect. Moreover, the ability of the GSB-106 dipeptide dimer to phosphorylate TrkB was selective, since no neuroprotective activity of GSB-106 was found in aPC12 cell line not expressing the full-length TrkB but expressing other neurotrophin receptors [23].…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we found that GSB-106, the mimetic of BDNF, activates TrkB and its ER K and the AKT signaling pathways [23] involved in neuronal survival and this fact could presumably underly its antidepressant effect. Moreover, the ability of the GSB-106 dipeptide dimer to phosphorylate TrkB was selective, since no neuroprotective activity of GSB-106 was found in aPC12 cell line not expressing the full-length TrkB but expressing other neurotrophin receptors [23]. …”

Section: Resultsmentioning

confidence: 99%

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Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF

et al. 2013

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A large amount of clinical and experimental data suggest the involvement of neurotrophins, in particular the brain-derived neurotrophic factor (BDNF), in depression pathogenesis. However, the therapeutic use of BDNF is limited because of its instability in biological fluids, poor blood-brain barrier (BBB) permeability, and the presence of side effects. A low-molecular-weight mimetic GSB-106, which is a substituted dimeric dipeptide bis(N-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide, was designed and synthesized based on the BDNF fourth loop structure at the V.V. Zakusov Institute of Pharmacology (RAMS). GSB-106 was found to exhibit an antidepressant activity in various models of depressive-like state when administered intraperitoneally to outbred mice and rats. An effect for the substance, when administered daily for 4–5 days, was detected in the Porsolt forced swimming test (0.1 and 1.0 mg/kg) and in the tail suspension test in mice (1.0 and 1.5 mg/ kg). An effect for GSB-106 at doses of 0.1 and 0.5 mg/kg was observed after a single application in experiments on rats in the Nomura water wheel test. The obtained evidence supports the hypothesis on the involvement of BDNF in the pathogenesis of various depression conditions, thus opening prospects for searching for new original antidepressants.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF

et al. 2013

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“…A mimetic of the fourth loop of 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 [9]. GSB-106 was established to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways-PI3K/AKT and MAPK/ERK [10]. GSB-106 demonstrated antidepressant activity at intraperitoneal (i.p.)…”

Section: Introductionmentioning

confidence: 99%

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

Povarnina¹,

Firsova²,

Таллерова³

et al. 2019

Antidepressants - Preclinical, Clinical and Translational Aspects

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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.

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“…Western blot analysis revealed that GSB-106 activates BDNF-specific TrkB receptors and their post-receptor signaling pathways MAPK/ERK and PI3K/AKT [12, 16]. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally [15, 17].…”

Section: Introductionmentioning

confidence: 99%

Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor

Povarnina¹,

Garibova²,

Gudasheva³

et al. 2018

Acta Naturae

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Involvement of BDNF in the regulation of neuroplasticity and neurogenesis in the hippocampus, impairment of which underlies the pathophysiology of depression, makes this endogenous protein a promising object for the development of new-generation antidepressants with a neurophysiologically based mechanism of action. A low-molecular-weight BDNF mimetic, GSB-106 (a substituted dimeric dipeptide, bis-(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide), was designed and synthesized at the Zakusov Institute of Pharmacology. GSB-106 was found to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK/ERK and PI3K/AKT. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally. Because oral administration is preferable in the treatment of depression, which is associated with a prolonged duration and outpatient character of pharmacotherapy, we examined the antidepressant properties of GSB-106 administered orally as a pharmaceutical substance (PS) and in tablet dosage form (TDF). In the study, we used the Porsolt forced swim test in rats; a conventional antidepressant, Amitriptyline, was used as a reference drug. The antidepressant activity of GSB-106 was found to retain upon oral administration and to manifest at doses of 0.5–5.0 mg/kg for PS and 0.01–5.0 mg/kg for TDF. The effective dose of TDF was 50-fold lower than that of PS, and the efficacy of tableted GSB-106 exceeded that of Amitriptyline, the “gold standard” in antidepression care. Therefore, GSB-106, both as a substance and as a tablet dosage form, exhibits antidepressant activity when administered orally, which makes it a promising antidepressant agent, the first in the class of BDNF mimetics.

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Brain-derived neurotrophic factor loop 4 dipeptide mimetic GSB-106 activates TrkB, Erk, and Akt and promotes neuronal survival in vitro

Cited by 30 publications

References 12 publications

Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF

Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF

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

Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor

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