Skip to main content
SpringerLink
Log in

Synthetic Analogs of 6-Bromohypaphorine, a Natural Agonist of Nicotinic Acetylcholine Receptors, Reduce Cardiac Reperfusion Injury in a Rat Model of Myocardial Ischemia

  • BIOCHEMISTRY, BIOPHYSICS, AND MOLECULAR BIOLOGY
  • Published:
Doklady Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

The data available to date indicate that the activation of nicotinic acetylcholine receptors (nAChR) of α7 type can reduce heart damage resulting from ischemia and subsequent reperfusion. We have studied two new synthetic D-analogs of 6-bromohypaphorine, which are selective agonists of α7 nAChR, in a rat model of myocardial ischemia. Acute myocardial infarction in animals was induced by occlusion of the left coronary artery with its subsequent reperfusion under mechanical lung ventilation. It was found that one of the analogs was more active, and treatment with it at the onset of reperfusion statistically reduced infarct size. This analog also prevented changes in the concentration of potassium and sodium ions in the blood, occurring during occlusion/reperfusion injury. The data obtained indicate that hypaphorine analogs are promising for the development of drugs that reduce the adverse effects of myocardial infarction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

REFERENCES

  1. Yellon, D.M. and Hausenloy, D.J., Myocardial reperfusion injury, N. Engl. J. Med., 2007, vol. 357, pp. 1121–1135.

    Article  CAS  Google Scholar 

  2. Gunata, M. and Parlakpinar, H., A review of myocardial ischaemia/reperfusion injury: pathophysiology, experimental models, biomarkers, genetics, and pharmacological treatment, Cell Biochem. Funct., 2021, vol. 39, no. 2, pp. 190–217.

    Article  CAS  Google Scholar 

  3. La Croix, C., Freeling, J., Giles, A., et al., Deficiency of m-2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress, Am. J. Physiol.: Heart Circ. Physiol., 2008, vol. 294, pp. 810–820.

    Google Scholar 

  4. Lara, A., Damasceno, D.D., Pireset, R., et al., Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure, Mol. Cell. Biol., 2010, vol. 30, pp. 1746–1756.

    Article  CAS  Google Scholar 

  5. Intachai, K.C., Chattipakorn, S., Chattipakorn, N., et al., Revisiting the cardioprotective effects of acetylcholine receptor activation against myocardial ischemia/reperfusion injury, Int. J. Mol. Sci., 2018, vol. 19, no. 9, p. 2466.

    Article  Google Scholar 

  6. Li, D.L., Liu, B.H., Sun, L., et al., Alterations of muscarinic acetylcholine receptors-2, 4 and α7-nicotinic acetylcholine receptor expression after ischaemia/reperfusion in the rat isolated heart, Clin. Exp. Pharmacol. Physiol., 2010, vol. 37, no. 12, pp. 1114–1119.

    Article  CAS  Google Scholar 

  7. Mavropoulos, S.A., Khan, S.N., Levy, A.C.J., et al., Nicotinic acetylcholine receptor-mediated protection of the rat heart exposed to ischemia reperfusion, Mol. Med., 2017, vol. 23, pp. 120–133.

    Article  CAS  Google Scholar 

  8. Kasheverov, I.E., Shelukhina, I.V., Kudryavtsev, D.S., et al., 6-Bromohypaphorine from marine nudibranch mollusk Hermissenda crassicornis is an agonist of human α7 nicotinic acetylcholine receptor, Mar. Drugs, 2015, vol. 13, pp. 1255–1266.

    Article  CAS  Google Scholar 

  9. Zhang, Y., Gu, E., Zhang, J., et al., Role of p38 mitogen activated protein kinases in cardioprotection of morphine preconditioning, Chin. Med. J., 2007, vol. 120, pp. 777–781.

    Article  CAS  Google Scholar 

  10. Schwarz, E.R., Somoano, Y., Hale, S.L., et al., What is the required reperfusion period for assessment of myocardial infarction size using triphenyltetrazolium chloride staining in the rat, J. Thromb. Thrombolysis, 2000, vol. 10, pp. 181–187.

    Article  CAS  Google Scholar 

  11. Kaneko, N., Okano, H., and Sawamoto, K., Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb, Genes Cells, 2006, vol. 11, no. 10, pp. 1145–1159.

    Article  CAS  Google Scholar 

  12. Mashimo, M., Iwasaki, Y., Inoue, S., et al., Acetylcholine released from T cells regulates intracellular Ca2+, IL-2 secretion and t cell proliferation through nicotinic acetylcholine receptor, Life Sci., 2017, vol. 172, pp. 13–18.

    Article  CAS  Google Scholar 

  13. Picciotto, M.R. and Zoli, M., Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, Front. Biosci., 2008, vol. 13, pp. 492–504.

    Article  CAS  Google Scholar 

  14. Echeverria, V., Yarkov, A., and Aliev, G., Positive modulators of the α7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer’s disease, Prog. Neurobiol., 2016, vol. 144, pp. 142–157.

    Article  CAS  Google Scholar 

  15. Shen, J.X. and Yakel, J.L., Functional alpha7 nicotinic ACh receptors on astrocytes in rat hippocampal CA1 slices, J. Mol. Neurosci., 2012, vol. 48, pp. 14–21.

    Article  CAS  Google Scholar 

  16. Corradi, J. and Bouzat, C., Understanding the bases of function and modulation of α7 nicotinic receptors: implications for drug discovery, Mol. Pharmacol., 2016, vol. 90, pp. 288–299.

    Article  CAS  Google Scholar 

  17. Levin, E.D., α7-Nicotinic receptors and cognition, Curr. Drug Targets, 2012, vol. 13, pp. 602–606.

    Article  CAS  Google Scholar 

  18. Yue, Y., Liu, R., Cheng, W., et al., GTS-21 attenuates lipopolysaccharide-induced inflammatory cytokine production in vitro by modulating the Akt and NF-κB signaling pathway through the α7 nicotinic acetylcholine receptor, Int. Immunopharmacol., 2015, vol. 29, no. 2, pp. 504–512.

    Article  CAS  Google Scholar 

  19. Egea, J., Buendia, I., Parada, E., et al., Anti-inflammatory role of microglial alpha7 nAChRs and its role in neuroprotection, Biochem. Pharmacol., 2015, vol. 97, pp. 463–472.

    Article  CAS  Google Scholar 

  20. Moens, A.L., Clayes, M.J., and Timmermans, J.P., Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process, J. Cardiol., 2005, vol. 100, pp. 179–190.

    CAS  Google Scholar 

Download references

Funding

The study was financially supported by the Russian Science Foundation (project no. 21-14-00316).

Author information

Authors and Affiliations

  1. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Pushchino Branch, Russian Academy of Sciences, Pushchino, Russia

    E. R. Shaykhutdinova, A. E. Kondrakhina, I. A. Dyachenko & A. N. Murashev

  2. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    I. A. Ivanov, D. S. Kudryavtsev,  V. I. Tsetlin & Yu. N. Utkin

Authors
  1. E. R. Shaykhutdinova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. E. Kondrakhina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. A. Ivanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. S. Kudryavtsev
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I. A. Dyachenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. N. Murashev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. I. Tsetlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu. N. Utkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu. N. Utkin.

Ethics declarations

Conflict of interest. The authors declare that they have no conflicts of interest.

Statement on the welfare of animals. All procedures were approved by the Commission for Control over the Housing and Use of Laboratory Animals of the Pushchino Branch of Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences (protocol-application no. 766/20).

Additional information

Translated by M. Batrukova

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shaykhutdinova, E.R., Kondrakhina, A.E., Ivanov, I.A. et al. Synthetic Analogs of 6-Bromohypaphorine, a Natural Agonist of Nicotinic Acetylcholine Receptors, Reduce Cardiac Reperfusion Injury in a Rat Model of Myocardial Ischemia. Dokl Biochem Biophys 503, 47–51 (2022). https://doi.org/10.1134/S1607672922020132

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1607672922020132

Keywords:

Search

Navigation