Pharmacology complex compound of pro-gly-pro-leu with heparin: hypoglycemic, fibrinolitic and anticoagulant effects in rats with hyperglycemia


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Abstract

Previously it was shown that the use of regulatory peptides of the glyprolin family helps to normalize the hemostasis system and blood glucose levels in experimental resistant hyperglycemia in rats, similar to type 2 diabetes mellitus in humans. It is also known that the anticoagulant heparin inhibits blood coagulation and exhibits a hypoglycemic effect in the body.The aim of the study is to obtain a complex of the Pro-Gly-Pro-Leu (PGPL) peptide and the unfractionated heparin, to study its effect on glucose and anticoagulant fibrinolytic properties and show its ability to restore the impaired functions of the insular and coagulating blood systems in experimental hyperglycemia in rats.Materials and Methods. Laboratory Wistar male rats, intact and with experimentally induced hyperglycemia, were used in the experiment. A complex compound of PGPL and heparin was created with a component ratio of 1:1 (mol/mol), which was administered intranasally to hyperglycemic rats once a day for 5 days at the dose of 1 mg/kg. Similarly, the constituent parts of the complex were administrated in equivalent amounts. The anticoagulant activity was determined by the test of activated partial thromboplastin time, fibrinolysis parameters - by tests of total, enzymatic and non-enzymatic fibrinolytic activities, as well as the activity of a tissue plasminogen activator. In addition, blood glucose was measured using special test strips. Results. The use of the PGPL-heparin complex in the animals with hyperglycemia led to normalization of blood glucose levels, an increase in the anticoagulant and fibrinolytic background of blood plasma. These effects persisted for 6 days after the cancellation of the peptide-heparin complex administration to rat.Conclusion. In the development of experimental hyperglycemia, the PGPL complex with heparin exhibits a combined hypo-glycemic, anticoagulant and fibrinolytic enzymatic and non-enzymatic nature of the effect. In the future, the studied peptide-heparin complex can be used for the prevention and treatment of type 2 diabetes mellitus, complicated by increased blood coagulation.

About the authors

T. Yu. Obergan

Lomonosov Moscow State University, Faculty of Biology

Email: tobergan@mail.ru
Laboratory of protective blood systems n. a. prof. B.A. Kudryashov

N. F. Myasoedov

Lomonosov Moscow State University, Faculty of Biology

Email: E-mail-nfm@img.ras.ru
Laboratory of protective blood systems n. a. prof. B.A. Kudryashov

M. E. Grigorjeva

Lomonosov Moscow State University, Faculty of Biology

Email: mgrigorieva@mail.ru
Laboratory of protective blood systems n. a. prof. B.A. Kudryashov

L. A. Lyapina

Lomonosov Moscow State University, Faculty of Biology

Email: lyapinal@mail.ru
Laboratory of protective blood systems n. a. prof. B.A. Kudryashov

T. A. Shubina

Lomonosov Moscow State University, Faculty of Biology

Email: shubina@mail.ru
Laboratory of protective blood systems n. a. prof. B.A. Kudryashov

L. A. Andreeva

Institute of Molecular Genetics, Russian Academy of Sciences

Email: landr@img.ras.ru

References

  1. Blair M. Diabetes mellitus review // Urol. Nurs. 2016. Vol. 36. P. 27-36.
  2. Ahren B., Schweizer A., Dejager S., Dunning B.E., Nillson P.M., Persson M., Foley J.E. Vildagliptin enhances islet responsiveness to both hyper- and hypoglycemia in patients with type 2 diabetes // J. Clin. Endocrinol. Metab. 2009. Vol. 94. P. 1236-1243.
  3. Мясоедов Н.Ф., Андреева Л.А., Ляпина Л.А., Ульянов А.М., Шубина Т.А., Оберган Т.Ю., Пасторова В.Е., Григорьева М.Е. Изучение сочетанного антидиабетогенного и противосвертывающего действия трипептида Gly-Pro-Arg на модели развития стойкой гипергликемии у крыс // Докл. Акад. Наук 2011. Т. 438. №2. С. 275-278.
  4. Шубина Т.А., Мясоедов Н.Ф., Андреева Л.А., Ляпина Л.А., Ульянов А.М., Оберган Т.Ю., Пасторова В.Е. Антикоагулянтно-фибринолитическая и гипогликемическая активность тетрапептида ARG-PRO-GLY-PRO // Бюлл. эксп. биол. и мед. 2012. Т. 153. №. 3. С. 304-307.
  5. Mulukutla S.N., Hsu J.W., Gaba R., Bohren K.M., Guthikonda A., Iyer D., Ajami N.J., Petrosino J.F., Hampe C.S., Ram N., Jahoor F., Balasubramanyam A. Arginin metabolism is altered in adults with a-в + ketosis-prone diabetes // J. Nutr. 2018. Vol.148. № 2. P. 185-193. doi: 10.1093/jn/nxx032.
  6. Brunetta S.H., de Camargo C.Q., Nunes E.A. Does L-leucine supplementation cause any effect on glucose homeostasis in rodent models of glucose intolerance? A systematic review // Amino Acids 2018. Vol. 15. P. 1663-1678. doi: 10.1007/s00726-018-2658-8.
  7. Golla K.I., Stavropoulos D., Shields D.S., Moran N.R. Peptides derived from cadherin juxta membrane region inhibit platelet function // Soc. Open Sci. 2018. Vol. 5. doi: 10.1098/rsos.172347.
  8. Мясоедов Н.Ф., Андреева Л.А., Ляпина Л.А., Шубина Т.А., Григорьева М.Е., Оберган Т.Ю. Коррекция нарушений противосвертывающей и инсулярной систем организма пептидом Leu-Pro-Gly-Pro // Изв. РАН Сер. биол. 2013. № 3. С. 341-344.
  9. Оберган Т.Ю., Шубина Т.А., Григорьева М.Е., Ляпина Л.А., Мясоедов Н.Ф., Андреева Л.А., Пасторова В.Е. Участие пептида Pro-Gly-Pro-Leu в востановлении функций противосвертывающей и инсулярной систем организма при развитии стойкой гипергликемии у крыс // Вопр.биол, мед. и фармац.хим. 2013. №4. С. 38-42.
  10. Aster R.H. Heparin-induced immune thrombocytopenia - a clinical or laboratory diagnosis? // J. Thromb. Haemost. 2006. Vol. 4. P. 757-758.
  11. Ляпина Л.А., Оберган Т.Ю., Пасторова В.Е. Регуляторная роль соединений гепарина с низкомолекулярными лигандами крови в плазменном и тромбоцитарном гемостазе // Изв. РАН Сер. Биол. 2011. № 2. С. 208-219.
  12. Смолина Т.Ю., Пасторова В.Е., Ляпина Л.А. Комплексо-образование дипептида пролил-глицин с гепарином: исследование гемостатических свойств комплекса in vitro при внутривенном введении // Тромбоз, гемостаз и реология. 2002. № 2. С. 38-41.
  13. Ляпина Л.А., Мясоедов Н.Ф., Андреева Л.А., Оберган Т.Ю., Шубина Т.А., Григорьева М.Е., Пасторова В.Е. Комплекс гепарина с пептидом Arg-Pro-Gly-Pro и его антикоагулянтно-фибринолитические и гипогликемические эффекты // Изв. РАН Сер. биол. 2012. № 1. С. 72-77.
  14. Ляпина Л.А., Григорьева М.Е., Оберган Т.Ю., Шубина Т.А. Теоретические и практические вопросы изучения функционального состояния противосвертывающей системы крови. М.: ООО «Адвансед солюшин». 2012. 159 стр.
  15. Dedov I.I., Shestakova M.V., Shestakova O.Y. Innovation in the treatment of type 2 diabetes mellitus: use of incretins // Ter. Arkh. 2010. Vol. 82. P. 5-10.
  16. Lyapina L.A, Pastorova V.E., G.E. Samonina G.E., Ashmarin I.P. The effect of prolil-glycil-proline (PGP) peptide and PGP-rich substances on haemostatic parameters of rat blood // Blood Coagul. and Fibrinol. 2000 Vol. 11 P. 409-414.
  17. Stief T.W. Inhibition of thrombin in plasma by heparin or arginine // Clin. Appl. Thromb. Hemost. 2007. Vol. 13 P. 146-153.
  18. Myasoedov N.F., Rochev D.L., Lyapina L.A., Obergan T.Y., Andreeva L.A. Leucine-containing glyprolines (Pro-Gly-Pro-Leu and Leu-Pro-Gly-Pro): participation in hemostatic reactions in vitro and in vivo in rats with blood coagulation and lipid metabolism disorders // Dokl. Biol. Sci. 2013. Vol. 453. P. 345-348.
  19. Valencia-Mejia E., Batista K.A., Fernandes J.J.A., Fernandes K.F. Antihyperglycemic and hypoglycemic activity of naturally occurring peptides and protein hydrolysates from easy-to-cook and hard-to-cook beans (Phaseolus vulgaris) // Food Res. Int. 2019. Vol. 121. P. 238-246. doi: 10.1016/j.foodres.2019.03.043.
  20. Kvapil M. Strategy and tactics of treatment of type 2 diabetes mellitus // Vnitr. Lek. 2019. Vol. 65. № 4. P. 273-278.

Copyright (c) 2019 Obergan T.Y., Myasoedov N.F., Grigorjeva M.E., Lyapina L.A., Shubina T.A., Andreeva L.A.

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This work is licensed under a Creative Commons Attribution 4.0 International License.
 

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