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Cardiovascular Toxicology

, Volume 19, Issue 6, pp 510–517 | Cite as

Therapeutic Effects of Liraglutide, Oxytocin and Granulocyte Colony-Stimulating Factor in Doxorubicin-Induced Cardiomyopathy Model: An Experimental Animal Study

  • Emin TaşkıranEmail author
  • Mümin Alper Erdoğan
  • Gürkan Yiğittürk
  • Oytun Erbaş
Article

Abstract

Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague–Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 μg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 μg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001) the highest ECG QRS wave voltage amplitude (0.21 ± 0.008 mV) (p < 0.00001) least plasma MDA (115.3 ± 19.8 nm) (p < 0.001), TNF-alpha (26.6 ± 3.05 pg/ml) (p < 0.001), pentraxin-3 (2.7 ± 0.9 ng/ml) (p < 0.001), Troponin T (1.4 ± 0.08 pg/ml) (p < 0.001), pro-BNP (11.1 ± 3.6 pg/ml) (p < 0.001) levels among all three treatment groups. Consistent with previous literature, we found that OX treatment decreased oxidative, apoptotic and inflammatory activity in DXR-induced cardiomyopathy rat model as well as provided better tissue integrity and better results in clinically relevant measures of ECG assessment, plasma Troponin T and pro-BNP levels. LIR and G-CSF treatment caused similar results with less powerful effects. Our findings suggest that with the best results in OX treatment group, all three agents including LIR and G-CSF attenuates DXR-induced cardiomyopathy in this rat model.

Keywords

Doxorubicin Cardiotoxicity Liraglutide Oxytocin G-CSF Inflammation 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors did not declare any conflict of interest.

References

  1. 1.
    Octavia, Y., Tocchetti, C. G., Gabrielson, K. L., Janssens, S., Crijns, H. J., & Moens, A. L. (2012). Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. Journal of Molecular and Cellular Cardiology, 52, 1213–1225.CrossRefGoogle Scholar
  2. 2.
    Takemura, G., & Fujiwara, H. (2007). Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Progress in Cardiovascular Diseases, 49, 330–352.CrossRefGoogle Scholar
  3. 3.
    L’Ecuyer, T., Sanjeev, S., Thomas, R., Novak, R., Das, L., Campbell, W., et al. (2006). DNA damage is an early event in doxorubicin-induced cardiacmyocyte death. Am. J. Physiol Heart Circ. Physiol., 291, H1273–H1280.CrossRefGoogle Scholar
  4. 4.
    Wang, Y., & Yang, T. (2015). Liraglutide reduces oxidized DL induced oxidative stress and fatty degeneration in raw 264.7 cells involving the AMPK/SREBP1 pathway. J of Geriatric Cardiology, 12, 410–416.Google Scholar
  5. 5.
    Zhu, H., Zhang, Y., Shi, Z., Lu, D., Li, T., Ding, Y., et al. (2016). The neuroprotection of liraglutide against ischemia-induced apoptosis through the activation of the PI3k/Akt and MAP pathways. Scientific Reports.  https://doi.org/10.1038/srep26859.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Biyikli, N. K., Tugtepe, H., Sener, G., Velioglu-Ogunc, A., Cetinel, S., & Midillioglu, S. (2006). Oxytocin alleviates oxidative renal injury in pyelonephritic rats via a neutrophil-dependent mechanism. Peptides, 27, 2249–2257.CrossRefGoogle Scholar
  7. 7.
    Erbas, O., Oltulu, F., & Taskiran, D. (2012). Amelioration of rotenone-induced dopaminergic cell death in the striatum by oxytocin treatment. Peptides, 38, 312–317.  https://doi.org/10.1016/j.peptides.2012.05.026.CrossRefPubMedGoogle Scholar
  8. 8.
    Song, S., Sava, V., Rowe, A., Li, K., Cao, C., Mori, T., et al. (2011). Granulocyte-colony stimulating factor (G-CSF) enhances recovery in mouse model of Parkinson’s disease. Neuroscience Letters, 487, 153–157.CrossRefGoogle Scholar
  9. 9.
    Ha, Y., Park, H. S., Park, C. W., Yoon, S. H., Park, S. R., Hyun, D. K., et al. (2005). Granulocyte macrophage colony stimulating factor (GM-CSF) prevents apoptosis and improves functional outcome in experimental spinal cord contusion injury. Clinical Neurosurgery, 52, 341–347.PubMedGoogle Scholar
  10. 10.
    Wallace, K. B. (2003). Doxorubicin-induced cardiac mitochondrionopathy. Pharmacology and Toxicology, 93, 105–115.CrossRefGoogle Scholar
  11. 11.
    Demougeot, C., Marie, C., & Beley, A. (2000). Importance of iron location in iron-induced hydroxyl radical production by brain slices. Life Sciences, 67, 399–410.CrossRefGoogle Scholar
  12. 12.
    Dimitrakis, P., Romay-Ogando, M. I., Timolati, F., Suter, T. M., & Zuppinger, C. (2012). Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes. Cell and Tissue Research, 350, 361–372.CrossRefGoogle Scholar
  13. 13.
    Von Hoff, D. D., Layard, M. W., Basa, P., Davis, H. L., Jr., Von Hoff, A. L., Rozencweig, M., et al. (1979). Risk factors for doxorubicin-induced congestive heart failure. Annals of Internal Medicine, 91, 710–717.CrossRefGoogle Scholar
  14. 14.
    Swain, S. M., Whaley, F. S., & Ewer, M. S. (2003). Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer, 97, 2869–2879.CrossRefGoogle Scholar
  15. 15.
    Lefrak, E., Pit’ha, J., Rosenheim, S., & Gottlieb, J. (1973). A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer, 32, 302–314.CrossRefGoogle Scholar
  16. 16.
    Aleman, B. M. P., Moser, E. C., Nuver, J., Suter, T. M., Maraldo, M. V., Specht, L., et al. (2014). Cardiovascular disease after cancer therapy. European Journal of Cancer Supplements, 12, 18–28.CrossRefGoogle Scholar
  17. 17.
    Aryal, B., Jeong, J., & Rao, V. A. (2014). Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity. Proceedings of the National Academy of Sciences of the USA, 111(5), 2011–2016.CrossRefGoogle Scholar
  18. 18.
    Sharma, P., Jha, A. B., Dubey, R. S., & Pessarakli, M. (2012). Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions. Journal of Botany, 2012, 26.CrossRefGoogle Scholar
  19. 19.
    Kotamraju, S., Konorev, E. A., Joseph, J., & Kalyanaraman, B. (2000). Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. Journal of Biological Chemistry, 275, 33585–33592.CrossRefGoogle Scholar
  20. 20.
    Wu, S., et al. (2002). Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: In vitro and in vivo studies. Journal of Molecular and Cellular Cardiology, 34, 1595–1607.CrossRefGoogle Scholar
  21. 21.
    Niu, J., Azfer, A., Wang, K., Wang, X., & Kolattukudy, P. E. (2009). Cardiac-targeted expression of soluble fas attenuates doxorubicin-induced cardiotoxicity in mice. Journal of Pharmacology and Experimental Therapeutics, 328, 740–748.  https://doi.org/10.1124/jpet.108.146423.CrossRefGoogle Scholar
  22. 22.
    Akdemir, A., Erbas, O., Gode, F., Ergenoglu, M., Yeniel, O., Oltulu, F., et al. (2014). Protective effect of oxytocin on ovarian ischemia-reperfusion injury in rats. Peptides, 55, 126–130.CrossRefGoogle Scholar
  23. 23.
    Akman, T., Akman, L., Erbas, O., Terek, M. C., Taskiran, D., & Ozsaran, A. The preventive effect of oxytocin to cisplatin-induced neurotoxicity: An experimental rat model. BioMed Research International, 2015, Article ID 167235Google Scholar
  24. 24.
    Erbas, O., Taşkıran, D., Oltulu, F., Yavaşoğlu, A., Bora, S., Bilge, O., et al. (2017). Oxytocin provides protection against diabetic polyneuropathy in rats. Neurological Research, 39(1), 45–53.  https://doi.org/10.1080/01616412.2016.1249630.CrossRefPubMedGoogle Scholar
  25. 25.
    Gao, H., Hu, L., Li, D., et al. (2013). Effects of glycagon like peptide-1 on liver oxidative stress, TNFα and TGF-β1 in rats with non-alcoholic fatty liver disease. Nan FangYi Ke DaXue Xue Bao, 33, 1661–1664. (In Chinese).Google Scholar
  26. 26.
    Li, Y., Hansotia, T., Yusta, B., Ris, F., Halban, P. A., & Drucker, D. J. (2003). Glycagon-like peptide-1 receptor signaling modulates beta cell apoptosis. Journal of Biological Chemistry, 278, 471–478.CrossRefGoogle Scholar
  27. 27.
    Abbas, A. T. N., & Kabil, L. S. (2017). Liraglutide ameliorates cardiotoxicity induced by doxorubicin in rats through the Akt/GSK-3β signaling pathway. Naunyn-Schmiedeberg’s Archives of Pharmacology, 390, 1145–1153.CrossRefGoogle Scholar
  28. 28.
    Shyu, W. C., Lin, S. Z., Yang, H. I., Tzeng, Y. S., Pang, C. Y., Yen, P. S., et al. (2004). Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation, 110, 1847–1854.CrossRefGoogle Scholar
  29. 29.
    Shyu, W. C., Lin, S. Z., Lee, C. C., Liu, D. D., & Li, H. (2006). Granulocyte colony-stimulating factor for acute ischemic stroke: A randomized controlled trial. CMAJ, 174, 927–933.CrossRefGoogle Scholar
  30. 30.
    Hartung, T. (1998). Anti-inflammatory effects of granulocyte colony-stimulating factor. Current Opinion in Hematology, 5, 221–225.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Geriatrics, Faculty of MedicineEge UniversityIzmirTurkey
  2. 2.Department of Physiology, Faculty of MedicineKatip Çelebi UniversityIzmirTurkey
  3. 3.Department of Histology and Embryology, Faculty of MedicineSıtkı Koçman UniversityMuğlaTurkey
  4. 4.Department of Physiology, Faculty of MedicineBilim UniversityIstanbulTurkey

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