NOOTROPICACTIVITY OF BRAIN-DERIVED NEUROTROPHIC FACTOR DIPEPTIDE MIMETIC GSB-106

DOI: https://doi.org/10.29296/25877313-2020-01-03
Issue: 
1
Year: 
2020

P.Yu. Povarnina Ph.D. (Biol.), V.V. Zakusov Research Institute of Pharmacology (Moscow) E-mail: povarnina@gmail.com D.M. Nikiforov Ph.D. (Biol.), V.V. Zakusov Research Institute of Pharmacology (Moscow) S.O. Kotelnikova Ph.D. (Biol.), V.V. Zakusov Research Institute of Pharmacology (Moscow) V.A. Kraineva Ph.D. (Biol.), V.V. Zakusov Research Institute of Pharmacology (Moscow) T.A. Guydasheva Dr.Sc. (Biol.), Professor, V.V. Zakusov Research Institute of Pharmacology (Moscow) S.B. Seredenin Dr.Sc. (Med.), Professor, V.V. Zakusov Research Institute of Pharmacology (Moscow)

A potential antidepressant based on the BDNF loop 4 dipeptide mimetic GSB-106, bis-(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, is de-veloping at the V.V. Zakusov Research Institute of Pharmacology.It is well known that depression is often accompanied by cognitive impairment. The aim of this investigation was to study the nootropic activity of GSB-106. The effect of GSB-106 dipeptide on memory was studied upon subchronicintra-peritoneal (ip) administration to unbred male ratsusing novel object recognition testand passive avoidance reflex amnesia caused by maximum elec-troshock (MES).GSB-106 was administered at a dose of 0.1 mg/kg (ip) for 14 days before the object recognition test and at doses of 0.1 and 1.0 mg/kg (ip) for 5 days before passive avoidance reaction training. It was found that GSB-106 at a dose of 0.1 mg / kg improves working memory in the novel object recognition test, increasing the relative time of investigation of an unfamiliar object, and at a dose of 1.0 mg / kg shows a pronounced antiam-nestic activity with a therapeutic effect of about 60% in the passive avoidance reaction test with amnesia caused by MES. Thus, the dipeptide mimetic of the BDNF loop 4 GSB-106 exhibits nootropic activity.

Keywords: 
dipeptide mimetic
BDNF
GSB-106
nootropic activity
passive avoidance test
novel object recognition test

References: 
  1. Nagahara A.H., Tuszynski M.H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov. 2011; 10(3):209–219.
  2. Tejeda G.S., Díaz-Guerra M. Integral сharacterization of defective BDNF/TrkB signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci. 2017; 8(2):124.
  3. Björkholm C., Monteggia L.M. BDNF  A key transducer of antidepressant effects. Neuropharmacology. 2016; 102:72–79.
  4. Gudasheva T.A., Tarasyuk A.V., Pomogajbo S.V., Logvinov I.O., Povarnina P.Yu., Antipova T.A., Seredenin S.B. Dizajn i sintez dipeptidnyh mimetikov mozgovogo nejrotroficheskogo faktora. Bioorganicheskaya himiya. 2012; 38(3): 280–290.
  5. Gudasheva T.A., Logvinov I.O., Antipova T.A., Seredenin S.B. Dipeptidnyj mimetik 4-j petli mozgovogo nejrotroficheskogo faktora GSB-106 aktiviruet TrkB, Erk, Akt i sposobstvuet vyzhivaemosti nejronov in vitro. Doklady akademii nauk. 2013; 451(5):577–580.
  6. Seredenin S.B., Voronina T.A., Gudasheva T.A., Garibova T.L., Molodavkin G.M., Litvinova S.A., Elizarova O.A., Poseva V.I. Antidepressivnyj effekt original'nogo nizkomolekulyarnogo mimetika BDNF, dimernogo dipeptida GSB-106. Acta Naturae. 2013; 4(19):116–120.
  7. Povarnina P.Yu., Garibova T.L., Gudasheva T.A., Seredenin S.B. Dipeptidnyj mimetik mozgovogo nejrotroficheskogo faktora obladaet svojstvami antidepressanta pri peroral'nom vvedenii. Acta Naturae. 2018; 10(3):88–92.
  8. Gudasheva T.A., Povarnina P, Tallerova A.V., Seredenin S.B. Antidepressant-like activity of dimeric dipeptide mimetics of different BDNF hairpin loops is determined by the activation pattern of TrkB receptor signaling pathways. Int. J. Pharma Sci & Sci Res. 2018; 4(7):6267.
  9. Gudasheva T.A., Povarnina P.Yu., Seredenin S.B. Dipeptidnyj mimetik mozgovogo nejrotroficheskogo faktora predotvrashchaet narushenie nejrogeneza u stressirovannyh myshej. Byulleten' eksperimental'noj biologii i mediciny. 2016; 162(10):448–451.
  10. Gudasheva T.A., Povarnina P.Yu., Antipova T.A., Seredenin S.B. Dipeptidnyj mimetik BDNF GSB-106 s antidepressivnoj aktivnost'yu stimuliruet sinaptogenez. Doklady akademii nauk. 2018; 481(6):691–693.
  11. Gudasheva T.A., Povarnina P., Logvinov I.O., Antipova T.A., Seredenin S.B. Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rat. Drug Des Devel Ther. 2016; 10:3545–353.
  12. Gudasheva T.A., Konstantinopol'skij M.A., Tarasyuk A.V., Kolik L.G., Seredenin S.B. Dipeptidnyj mimetik 4-j petli mozgovogo nejrotroficheskogo faktora obladaet anal'geticheskoj aktivnost'yu. Doklady akademii nauk. 2019; 485(3):366369.
  13. Lam R.W., Kennedy S.H., Mclntyre R.S., Khullar A. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can. J. Psychiatry. 2014; 59(12):649–654.
  14. Bekinschtein P., Cammarota M., Medina J.H. BDNF and memory processing. Neuropharmacology. 2014; 76:677–683.
  15. Ma L., Wang D.D., Zhang T.Y., Yu H., Wang Y., Huang S.H., Lee F.S., Chen Z.Y. Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation. J. Neurosci. 2011; 31(6):2079–2090.
  16. Ennaceur A., Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res. 1988; 31(1):4759.
  17. Klingberg T. Training and plasticity of working memory. Trends Cogn Sci. 2010; 14(7):317324.
  18. Beldjoud H., Barsegyan A., Roozendaal B. Noradrenergic activation of the basolateral amygdala enhances object recognition memory and induces chromatin remodeling in the insular cortex. Front Behav Neurosci. 2015; 9:108.
  19. Voronina T.A. Eksperimental'naya farmakologiya nootropov. M.: Medicina, 1989. S. 9198.
  20. Ader R., Weijnen J. A. W. M., Moleman P. Retention of a passive avoidance response as a function of the intensity and duration of electric shock. Psychon. Sci. 1972; 26:125–128.
  21. Wang Y., Zhang T.Y., Xin J., Li T., Yu H., Li N., Chen Z.Y. Differential involvement of brain-derived neurotrophic factor in reconsolidation and consolidation of conditioned taste aversion memory. PLoS One. 2012; 7(11):111.
  22. Bekinschtein P., Cammarota M., Katche C., Slipczuk L., Rossato J.I,. Goldin A, Izquierdo I., Medina J.H. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A. 2008; 105(7): 2711–2716.
  23. Rosas-Vidal L.E., Do-Monte F.H., Sotres-Bayon F., Quirk G.J. Hippocampal–prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology. 2014; 39(9): 2161–2169.
  24. Radiske A., Rossato J.I., Gonzalez M.C., Köhler C.A., Bevilaqua L.R., Cammarota M. BDNF controls object recognition memory reconsolidation. Neurobiol Learn Mem. 2017; 142:79–84.
  25. Bollen E., Vanmierlo T., Akkerman S., Wouters C., Steinbusch H.M.W., Prickaerts J. 7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice. Behav Brain Res. 2013; 257: 8–12.