Antidiabetic Properties of Low-Molecular-Weight BDNF Mimetics Depend on the Type of Activation of Post-Receptor Signaling Pathways

  • R. U. Ostrovskaya
  • S. S. Yagubova
  • T. A. Gudasheva
  • S. B. Seredenin
PHARMACOLOGY AND TOXICOLOGY
  • 6 Downloads

Reduced proliferation and enhanced apoptosis of β cells in diabetes mellitus are associated with a deficiency of brain-derived neurotrophic factor (BDNF). Low-molecular weight compounds similar to different BDNF loops were synthesized at the V. V. Zakusov Research Institute of Pharmacology. They produce a potentiating effect on TrkB phosphorylation, but differently activate post-receptor signaling pathways. We compared their effects on the severity of streptozotocin-induced diabetes mellitus in C57Bl/6 mice. The antidiabetic effect (estimated from the degree of hyperglycemia and dynamics of body weight) was typical of GSB-214 compound that selectively activates PI3K/Akt. This activity was not revealed in GTS-201, selective activator of MAPK/Erk. GSB-106 compound activating both signaling pathways exhibited weak antidiabetic activity. Our results indicate that the antidiabetic effect is mainly related to activation of the PI3K/Akt signaling pathway.

Key Words

diabetes C57Bl/6 mice streptozotocin low-molecular-weight BDNF mimetics 

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References

  1. 1.
    Gudasheva TA, Antipova TA, Konstantinopolsky MA, Povarnina PY, Seredenin SB. Nerve growth factor novel dipeptide mimetic GK-2 selectively activates TrkA postreceptor signaling pathways and does not cause adverse effects of native neurotrophin. Dokl. Biochem. Biophysics. 2014;456(1):88-91.Google Scholar
  2. 2.
    Gudasheva TA, Antipova TA, Seredenin SB. Novel low-molecular-weight mimetics of the nerve growth factor. Dokl. Biochem. Biophysics. 2010;434(1):262-265.Google Scholar
  3. 3.
    Gudasheva TA, Tarasyuk AB, Pomogaibo SV, Logvinov IO, Povarnina PYu, Antipova TA, Seredenin SB. Design and synthesis of dipeptide mimetics of the brain neurotrophic factor. Bioorgan. Khimiya. 2012;38(3):280-290.Google Scholar
  4. 4.
    Gudasheva TA, Tarasiuk AV, Sazonova NM, Povarnina PYu, Antipova TA, Seredenin SB. A Novel Dimeric Dipeptide Mimetic of the BDNF Selectively Activates the MAPK-Erk Signaling Pathway. Dokl. Biochem. Biophysics. 2017;476(1):291-295.CrossRefGoogle Scholar
  5. 5.
    Ostrovskaya RU, Yagubova SS, Gudasheva TA, Seredenin SB. Low-molecular-weight ngf mimetic corrects the cognitive deficit and depression-like behavior in experimental diabetes. Acta Naturae. 2017;9(2):94-102.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Patent RU No. 2613314. Small molecules with ngf-like activity and antidiabetic properties. Bull. No. 8. Published March 15, 2017.Google Scholar
  7. 7.
    Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch. Med. Sci. 2015;11(6):1164-1178.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gudasheva TA, Povarnina P, Logvinov IO, Antipova TA, Seredenin S.B. Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats. Drug Des. Devel. Ther. 2016;10:3545-3553.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gudasheva TA, Povarnina PYu, Seredenin SB. Dipeptide mimetic of the brain-derived neurotrophic factor prevents impairments of neurogenesis in stressed mice. Bull. Exp. Biol. Med. 2017;162(4):454-457.CrossRefPubMedGoogle Scholar
  10. 10.
    Hayashi K, Kojima R, Ito M. Strain differences in the diabetogenic activity of streptozotocin in mice. Biol. Pharm. Bull. 2006;29(6):1110-1119.CrossRefPubMedGoogle Scholar
  11. 11.
    Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 2000;10(3):381-391.CrossRefPubMedGoogle Scholar
  12. 12.
    Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, Fischer CP, Lindegaard B, Petersen AM, Taudorf S, Secher NH, Pilegaard H, Bruunsgaard H, Pedersen BK. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia. 2007;50(2):431-438.CrossRefPubMedGoogle Scholar
  13. 13.
    Nakagawa T, Tsuchida A, Itakura Y, Nonomura T, Ono M, Hirota F, Inoue T, Nakayama C, Taiji M, Noguchi H. Brainderived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice. Diabetes. 2000;49(3):436-444.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamanaka M, Itakura Y, Ono-Kishino M, Tsuchida A, Nakagawa T, Taiji M. Intermittent administration of brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism and prevents pancreatic exhaustion in diabetic mice. J. Biosci. Bioeng. 2008;105(4):395-402.CrossRefPubMedGoogle Scholar
  15. 15.
    Yanev S, Aloe L, Fiore M, Chaldakov GN. Neurotrophic and metabotrophic potential of nerve growth factor and brain-derived neurotrophic factor: Linking cardiometabolic and neuropsychiatric diseases. World J. Pharmacol. 2013;2(4):92-99.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • R. U. Ostrovskaya
    • 1
  • S. S. Yagubova
    • 1
  • T. A. Gudasheva
    • 1
  • S. B. Seredenin
    • 1
  1. 1.V. V. Zakusov Research Institute of PharmacologyMoscowRussia

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