Advertisement

Cardiometabolic Efficacy and Toxicological Evaluation of a Pharmacological Galanin Receptor Agonist

  • L. I. Serebryakova
  • M. E. Pal’keeva
  • I. M. Studneva
  • M. V. Ovchinnikov
  • O. M. Veselova
  • A. S. Molokoedov
  • A. A. Az’muko
  • E. V. Arzamastsev
  • E. Yu. Afanasyeva
  • O. A. Terekhova
  • M. V. Sidorova
  • O. I. PisarenkoEmail author
Article

Abstract—

The goal of this study was to examine effects of a novel galanin receptor agonist GalR1-3 [βAla14, His15]-galanine 2-15 (G), obtained by automatic solid-phase peptide synthesis, on the metabolic state of the area at risk and the size of acute myocardial infarction (MI) in rats in vivo and to evaluate its toxicity in BALB/c mice after a single dose administration. Regional ischemia was induced in anesthetized rats by coronary artery occlusion followed by restoration of coronary blood flow. The peptide G was administered intravenously (i.v.) with a bolus after a period of regional ischemia in the dose range of 0.25–3.0 mg/kg. The sizes of MI and activities of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in blood plasma were evaluated. The effect of administration of the optimal dose of G (1.0 mg/kg) on the myocardial content of adenine nucleotides (AN), phosphocreatine (PCr), creatine (Cr), and lactate was studied. The peptide G toxicity was evaluated after a single intraperitoneal injection of 0.5–3.0% solution of the peptide substance to mice. The i.v. administration of the optimal dose of G to rats (1.0 mg/kg) insignificantly influenced hemodynamic parameters, but reduced the MI size by 40% and decreased plasma LDH and CK-MB activity by the end of reperfusion as compared to control. These effects were accompanied by a significant improvement in the metabolic state of the area at risk (AAR) as evidenced by an increase in the myocardial content of ATP, ΣAN, PCr and ΣCr, and a decrease in the myocardial lactate level compared to control. The absence of signs of intoxication and death of animals after G injection of the maximum possible dose did not allow determining an LD50 dose. The results of this study indicate a therapeutic potential of the peptide G for preventing myocardial ischemia and reperfusion injury and a clear need for further studies of its pharmacological properties and mechanisms of action.

Keywords:

galanin rat myocardial ischemia and reperfusion myocardial energy metabolism toxicity 

Notes

FUNDING

This work was supported by the Russian Foundation for Basic Research (project nos. 18-015-00008 and 18-015-00009).

COMPLIANCE WITH ETHICAL STANDARDS

The study was carried out in accordance with the “International Recommendations for Biomedical Research Using Animals” approved by the Council for International Organizations of Medical Sciences (CIOMS) in 1985 (Geneva).

REFERENCES

  1. 1.
    Foster, S.R., Roura, E., Molenaar, P., and Thomas, W.G., Biophys. Rev., 2015, vol. 7, pp. 77–89.  https://doi.org/10.1007/s12551-014-0154-2 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wang, J., Gareri, C., and Rockman, H.A., Circ. Res., 2018, vol. 123, no. 6, pp. 716–735.  https://doi.org/10.1161/CIRCRESAHA.118.311403 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mitsukawa, K., Lu, X., and Bartfai, T., Cell. Mol. Life Sci., 2008, vol. 65, no. 12, pp. 1796–1805.  https://doi.org/10.1007/s00018-008-8153-8 CrossRefPubMedGoogle Scholar
  4. 4.
    Webling, K., Runesson, J., Bartfai, T., and Langel, U., Front. Endocrinol., 2012, vol. 7, no. 3, 146.Google Scholar
  5. 5.
    Abbott, S. and Pilowsky, P., Am. J. Physiol. Regul. Integr. Comp. Physiol., 2009, vol. 296, no. 4, pp. R1019–R1026.  https://doi.org/10.1152/ajpregu.90885.2008 CrossRefPubMedGoogle Scholar
  6. 6.
    He, B., Shi, M., Zhang, L. Li, G., Zhang, L., Shao, H., Li, J., Fang, P., Ma, Y., Shi, Q., and Sui, Y., Physiol. Behav., 2011, vol. 103, nos. 3–4, pp. 284–289.  https://doi.org/10.1016/j.physbeh.2011.02.023 CrossRefPubMedGoogle Scholar
  7. 7.
    Alston, E.N., Parrish, D.C., Hasan, W., Tharp, K., Pahlmeyer, L., and Habecker, B.A., Neuropeptides, 2011, vol. 45, no. 1, pp. 33–42.  https://doi.org/10.1016/j.npep.2010.10.002 CrossRefPubMedGoogle Scholar
  8. 8.
    Kocic, I., J. Pharm. Pharmacol., 1998, vol. 50, no. 12, pp. 1361–1364.  https://doi.org/10.1111/j.2042-7158.1998.tb03360.x CrossRefPubMedGoogle Scholar
  9. 9.
    Diaz-Cabiale, Z., Parrado, C., Vela, H., Razani, H., Coveñas, R., Fuxe, K., and Narváez, J.A., Neuropeptides, 2005, vol. 39, pp. 185–190.  https://doi.org/10.1016/j.npep.2004.12.009 CrossRefPubMedGoogle Scholar
  10. 10.
    Liu, H.X., Brumovsky, P., Schmidt, R., Brown, W., Payza, K., Hodzic, L., Pou, C., Godbout, C., and Hökfelt, T., Proc. Natl. Acad. Sci. USA, 2001, vol. 98, pp. 9960–9964.  https://doi.org/10.1073/pnas.161293598 CrossRefPubMedGoogle Scholar
  11. 11.
    Runesson, J., Saar, I., Lundström, L., Järv, J., and Langel, U., Neuropeptides, 2009, vol. 43, pp. 187–192.  https://doi.org/10.1016/j.npep.2009.04.004 CrossRefPubMedGoogle Scholar
  12. 12.
    Hua, X.Y., Hayes, C.S., Hofer, A., Fitzsimmons, B., Kilk, K., Langel, U., Bartfai, T., and Yaksh, T.L., J. Pharmacol. Exp. Ther., 2004, vol. 308, no. 2, pp. 574–582.  https://doi.org/10.1124/jpet.103.058289 CrossRefPubMedGoogle Scholar
  13. 13.
    Shulzhenko, V.S., Serebryakova, L.I., Studneva, I.M., Pelogejkina, Yu.A., Veselova, O.M., Molokoedov, A.S., Ovchinnikov, M.V., Palkeeva, M.E., Sidorova, M.V., and Pisarenko, O.I., Kardiologicheskii vestnik, 2016, vol. 11, no. 3, pp. 12–21.Google Scholar
  14. 14.
    Timotin, A., Pisarenko, O., Sidorova, M., Studneva, I., Shulzhenko, V., Palkeeva, M., Serebryakova, L., Molokoedov, A., Veselova, O., Cinato, M., Tronchere, H., Boal, F., and Kunduzova, O., Oncotarget, 2017, vol. 8, no. 13, pp. 21 241–21 252.  https://doi.org/10.18632/oncotarget.15071 CrossRefGoogle Scholar
  15. 15.
    Azmuko, A.A., Veselova, O.M., Molokoedov, A.S., Ovchinnikov, M.V., Palkeeva, M.E., Pisarenko, O.I., Serebryakova, L.I., Sidorova, M.V., and Studneva I.M., Rus Patent no. 2648846, registered March 28, 2018.Google Scholar
  16. 16.
    Palkeeva, M., Studneva, I., Molokoedov, A., Serebryakova, L., Veselova, O., Ovchinnikov, M., Sidorova, M., and Pisarenko, O., Biomed. Pharmacother., 2019, vol. 109, pp. 1556–1562.  https://doi.org/10.1016/j.biopha.2018.09.182 CrossRefPubMedGoogle Scholar
  17. 17.
    Studneva, I.M., Palkeeva, M.E., Veselova, O.M., Molokoedov, A.S., Lubimov, R.O., Ovchinnikov, M.V., Sidorova, M.V., and Pisarenko, O.I., Biomeditsinskaya khimiya, 2019, vol. 65, no. 1, pp. 51–56.  https://doi.org/10.18097/PBMC20196501051 CrossRefGoogle Scholar
  18. 18.
    Kitakaze, M., Takashima, S., Funaya, H., Minamino, T., Node, K., Shinozaki, Y., Mori, H., and Hori, M., Am. J. Physiol., 1997, vol. 272, pp. H2071–H2078.PubMedGoogle Scholar
  19. 19.
    Bergmeyer, H.U., Methods of Enzymatic Analysis, New York: Academic Press, 1974, pp. 1464–1467, 1772–1776, 1777–17781, 2127–2131.Google Scholar
  20. 20.
    Deichman, W.B. and Le Blanc, T.J., J. Indust. Hyg. Toxicol., 1943, vol. 25, no. 9, pp. 415–417.Google Scholar
  21. 21.
    Kaur, S., Jaggi, A.S., and Singh, N., Fundam. Clin. Pharmacol., 2009, vol. 23, no. 5, pp. 521–536.CrossRefGoogle Scholar
  22. 22.
    Lang, R., Gundlach, A.L., Holmes, F.E., Hobson, S.A., Wynick, D., Hökfelt, T., and Kofler, B., Pharmacol. Rev., 2015, vol. 67, pp. 118–175.  https://doi.org/10.1124/pr.112.006536 CrossRefPubMedGoogle Scholar
  23. 23.
    Ryazantseva, N.V., Novitskii, V.V., Kajgorodova, E.V., Chasovskikh, N.Yu., and Starikova, E.G., Uspekhi Fiziol. Nauk, 2009, vol. 40, no. 2, pp. 3–11.Google Scholar
  24. 24.
    Tian, R. and Abel, E.D., Circulation, 2001, vol. 103, no. 24, pp. 2961–2966.CrossRefGoogle Scholar
  25. 25.
    Hausenloy, D.J. and Yellon, D.M., Pharmacol. Ther., 2007, vol. 116, no. 2, pp. 173–191.CrossRefGoogle Scholar
  26. 26.
    Maslov, L.N., Mrochek, A.G., Khaliulin, I., Hanuš, L., Pei, J., and Zhang, Y., Vestnik RAMN, 2013, vol. 68, no. 1, pp. 10–20.Google Scholar
  27. 27.
    Garratt, K.N., Holmes, D.R., Molina-Viamonte, V., Reeder, G.S., Hodge, D.O., Bailey, K.R., Lobl, J.K., Laudon, D.A., and Gibbons, R.J., Am. Heart J., 1998, vol. 136, no. 2, pp. 196–204.CrossRefGoogle Scholar
  28. 28.
    Claeys, M.J., Bosmans, J., De Ceuninck, M., Beunis, A., Vergauwen, W., Vorlat, A., and Vrints, C.J., Am. J. Cardiol., 2004, vol. 94, no. 1, pp. 9–13.CrossRefGoogle Scholar
  29. 29.
    Ross, A.M., Gibbons, R.J., Stone, G.W., Kloner, R.A., and Alexander, R.W., J. Am. Coll. Cardiol., 2005, vol. 45, no. 11, pp. 1775–1780.CrossRefGoogle Scholar
  30. 30.
    Piot, C., Croisille, P., Staat, P., Thibault, H., Rioufol, G., Mewton, N., Elbelghiti, R., Cung, T.T., Bonnefoy, E., Angoulvant, D., Macia, C., Raczka, F., Sportouch, C., Gahide, G., Finet, G., André-Fouët, X., Revel, D., Kirkorian, G., Monassier, J.P., Derumeaux, G., and Ovize, M., N. Engl. J. Med., 2008, vol. 359, no. 5, pp. 473–481.CrossRefGoogle Scholar
  31. 31.
    Mewton, N., Croisille, P., Gahide, G., Rioufol, G., Bonnefoy, E., Sanchez, I., Cung, T.T., Sportouch, C., Angoulvant, D., Finet, G., André-Fouët, X., Derumeaux, G., Piot, C., Vernhet, H., Revel, D., and Ovize, M., J. Am. Coll. Cardiol., 2010, vol. 55, no. 12, pp. 1200–1205.CrossRefGoogle Scholar
  32. 32.
    Grishin, A.V., Yavorovsky, A.G., Charchyan, E.R., Fedulova, S.V., and Charnaya, M.A., Anesteziol. Reanimatol., 2016, vol. 61, no. 5, pp. 348–352.  https://doi.org/10.18821/0201-7563-2016-61-5-348-352 CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang, R., Shen, L., Xie, Y., Gen, L., Li, X., and Ji, Q., J. Cardiothorac. Surg., 2013, vol. 8, 76.  https://doi.org/10.1186/1749-8090-8-76 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • L. I. Serebryakova
    • 1
  • M. E. Pal’keeva
    • 1
  • I. M. Studneva
    • 1
  • M. V. Ovchinnikov
    • 1
  • O. M. Veselova
    • 1
  • A. S. Molokoedov
    • 1
  • A. A. Az’muko
    • 1
  • E. V. Arzamastsev
    • 1
  • E. Yu. Afanasyeva
    • 1
  • O. A. Terekhova
    • 1
  • M. V. Sidorova
    • 1
  • O. I. Pisarenko
    • 1
    Email author
  1. 1.National Medical Research Center for CardiologyMoscowRussia

Personalised recommendations