Sign in Register Submit Manuscript

Damray Home

Location: Home >> The Dipeptide Mimetic of the Neurotrophin-3 Loop 4, Compound GTS-302, Exhibits Antidepressant-Like Activity in a Mouse Social Defeat Stress Model

  • donwnload article

    Download Article

  • donwnload article

    Share Article

Article

The Dipeptide Mimetic of the Neurotrophin-3 Loop 4, Compound GTS-302, Exhibits Antidepressant-Like Activity in a Mouse Social Defeat Stress Model

P. Y. Povarnina, D. M. Nikiforov, T. A. Antipova, I. O. Logvinov, S. V. Nikolaev, A. V. Tarasiuk, N. M. Sazonova, T. A. Gudasheva*, V. L. Dorofeev

Federal State Budgetary Scientific Institution “Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies”, Moscow, Russia.

*Corresponding author: T. A. Gudasheva

Published: 10 May 2024 How to cite this paper

Abstract

Experimental and clinical data indicate the involvement of neurotrophin-3 (NT-3) in the pathogenesis of depression. A dimeric dipeptide mimetic of the NT-3 loop 4, bis-(N-gamma-hydroxybutyryl-L-glutamyl-L-asparagine) hexamethylenediamide (GTS-302), demonstrating antidepressant-like activity in the forced swimming test in mice (0.5-10 mg/kg, ip), was created at the Research Zakusov Institute of Pharmacology. The aim of this study was to investigate the antidepressant-like activity of the dipeptide GTS-302 in an experimental model of depression. Male C57Bl/6 mice were exposed to a 10-day social defeat stress. They received daily ip injections of the dipeptide GTS-302 at a dose of 1 mg/kg for the entire duration of the stress period. Following the stress, the sucrose preference test was conducted to assess anhedonia. Hippocampal tissue was then collected for the analysis of synaptic proteins (synaptophysin, PSD-95) and BDNF levels using Western blot analysis. In stressed mice, sucrose preference decreased by 16% compared to non-stressed controls, accompanied by an 18% reduction in hippocampal BDNF levels. Treatment with compound GTS-302 nearly completely counteracted these impairments. Therefore, the dipeptide mimetic of NT-3, GTS-302, holds promise as a potential antidepressant.

KEYWORDS: NT-3, dimeric dipeptide mimetic, GTS-302, depression, social defeat stress, anhedonia, BDNF

References

[1] Levy MJF, Boulle F, Steinbusch HW, van den Hove DLA, Kenis G, Lanfumey L. Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression. Psychopharmacology (Berl)., 2018 Aug; 235(8):2195-220.

[2] Silva F, Masella G, Madeira MF, Duarte CB, Santos M. TrkC Intracellular Signalling in the Brain Fear Network During the Formation of a Contextual Fear Memory. Mol Neurobiol., 2023 Jun; 60(6):3507-21.

[3] Agostinho FR, Réus GZ, Stringari RB, Ribeiro KF, Pfaffenseller B, Stertz L, et al. Olanzapine plus fluoxetine treatment increases Nt-3 protein levels in the rat prefrontal cortex. Neurosci Lett., 2011 Jun 22; 497(2):99-103.

[4] Shimazu K, Zhao M, Sakata K, Akbarian S, Bates B, Jaenisch R, et al. NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis. Learn Mem., 2006 May-Jun; 13(3):307-15.

[5] D'Amico D, Gener T, de Lagrán MM, Sanchez-Vives MV, Santos M, Dierssen M. Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear. Neuropsychopharmacology. 2017 Jan; 42(2):462-72.

[6] Martin-Iverson MT, Todd KG, Altar CA. Brain-derived neurotrophic factor and neurotrophin-3 activate striatal dopamine and serotonin metabolism and related behaviors: interactions with amphetamine. J Neurosci., 1994 Mar; 14(3 Pt 1):1262-70.

[7] Blöchl A, Sirrenberg C. Neurotrophins stimulate the release of dopamine from rat mesencephalic neurons via Trk and p75Lntr receptors. J Biol Chem., 1996 Aug 30;271(35):21100-7.

[8] Patz S, Wahle P. Neurotrophins induce short-term and long-term changes of cortical neurotrophin expression. Eur J Neurosci., 2004 Aug; 20(3):701-8.

[9] Canossa M, Griesbeck O, Berninger B, Campana G, Kolbeck R, Thoenen H. Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity. Proc Natl Acad Sci U S A., 1997 Nov 25; 94(24):13279-86.

[10] Yang T, Nie Z, Shu H, Kuang Y, Chen X, Cheng J, et al. The Role of BDNF on Neural Plasticity in Depression. Front Cell Neurosci., 2020 Apr 15; 14:82.

[11] Bothwell M. NGF, BDNF, NT3, and NT4. Handb Exp Pharmacol., 2014; 220:3-15.

[12] Ogłodek EA, Just MJ, Szromek AR, Araszkiewicz A. Melatonin and neurotrophins NT-3, BDNF, NGF in patients with varying levels of depression severity. Pharmacol Rep., 2016 Oct; 68(5):945-51.

[13] Sheldrick A, Camara S, Ilieva M, Riederer P, Michel TM. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals—a proof of concept study. Eur Psychiatry., 2017 Oct; 46:65-71.

[14] Shirayama Y, Chen AC, Nakagawa S, Russell DS, Duman RS. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci., 2002 Apr 15;22(8):3251-61.

[15] Tarasiuk AV, Sazonova NM, Melnikova MV, Pomogaybo SV, Logvinov IO, Nikolaev SV, et al. Design and synthesis of a nov-el dipeptide mimetic of the 4th loop of neurotrophin-3 and its pharmacological effects. Mendeleev Communications, 2023; 33:786-9.

[16] Gudasheva TA, Povarnina PY, Tarasiuk AV, Seredenin SB. Low-molecular mimetics of nerve growth factor and brain-derived neurotrophic factor: Design and pharmacological properties. Med Res Rev., 2021 Sep;41(5):2746-74.

[17] Nikiforov DM, Povarnina PY, Gudasheva TA, Nadorova AV, Kolik LG, Valdman EA, et al. The study of the spectrum of phar-macological activity of the new original NT-3 mimetic dipeptide GTS-302. Medical Academic Journal, 2023; 23(2):87-99.

[18] Kudryavtseva NN, Avgustinovich DF, Bondar NP, Tenditnik MV, Kovalenko IL. An experimental approach for the study of psychotropic drug effects under simulated clinical conditions. Curr Drug Metab., 2008 May; 9(4):352-60.

[19] Povarnina PY, Tallerova AV, Mezhlumian AG, Kruglov SV, Antipova TA, Gudasheva TA, et al. Dimeric dipeptide BDNF mimetic GSB-106 exhibits antidepressant-like activity upon single oral administration in mice under social stress model conditions. Eksp Klin Farmakol., 2020; 83:3-7.

[20] Scheggi S, De Montis MG, Gambarana C. Making Sense of Rodent Models of Anhedonia. Int J Neuropsychopharmacol, 2018 Nov 1; 21(11):1049-65.

[21] Cooper JA, Arulpragasam AR, Treadway MT. Anhedonia in depression: biological mechanisms and computational models. Curr Opin Behav Sci., 2018 Aug; 22:128-35.

[22] Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem., 1951 Nov; 193(1):265-75.

[23] Primo MJ, Fonseca-Rodrigues D, Almeida A, Teixeira PM, Pinto-Ribeiro F. Sucrose preference test: A systematic review of protocols for the assessment of anhedonia in rodents. Eur Neuropsychopharmacol, 2023 Dec; 77:80-92.

[24] Verharen JPH., de Jong JW, Zhu Y, Lammel S. A computational analysis of mouse behavior in the sucrose preference test. Nat Commun., 2023; 14:2419.

[25] Wulff AB, Cooper P, Kodjo E, Abel E, Thompson SM. How Sucrose Preference Is Gained and Lost

[26] Volkova AA, Povarnina PYu, Nikiforov DM, Gudasheva TA, Seredenin SB. Comparative study of the mnemotropic activity of dimeric dipeptide mimetics of individual NGF and BDNF loops using a new-object recognition test in rats. Pharmaceutical Chemistry Journal, 2022 Jul 09; 56:429-32.

[27] Roddy DW, Farrell C, Doolin K, Roman E, Tozzi L, Frodl T, et al. The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression. Biol Psychiatry, 2019 Mar 15;85(6):487-97.

[28] Masi G, Brovedani P. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs, 2011 Nov 1;25(11):913-31.

[29] Castrén E, Monteggia LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry, 2021 Jul 15; 90(2):128-36.

[30] Ji CH, Gu JH, Liu Y, Tang WQ, Guan W, Huang J, et al. Hippocampal MSK1 regulates the behavioral and biological responses of mice to chronic social defeat stress: Involving of the BDNF-CREB signaling and neurogenesis. Biochem Pharmacol., 2022 Jan; 195:114836.

How to cite this paper

P. Y. Povarnina, D. M. Nikiforov, T. A. Antipova, I. O. Logvinov, S. V. Nikolaev, A. V. Tarasiuk, N. M. Sazonova, T. A. Gudasheva, V. L. Dorofeev. The Dipeptide Mimetic of the Neurotrophin-3 Loop 4, Compound GTS-302, Exhibits Antidepressant-Like Activity in a Mouse Social Defeat Stress Model. International Journal of Medicine Frontiers, 2024, 7(1), 1-9.


Copyright © 2022 Damray Co., Ltd. Privacy Policy | Terms and Conditions