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Molecules 2018, 23(5), 1184; https://doi.org/10.3390/molecules23051184

The Cardioprotective Effect of Metformin in Doxorubicin-Induced Cardiotoxicity: The Role of Autophagy

1
Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Nagyerdei Krt 98, 4032 Debrecen, Hungary
2
Department of Anatomy, Histology and Embriology, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98, 4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Received: 12 April 2018 / Revised: 10 May 2018 / Accepted: 11 May 2018 / Published: 15 May 2018
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Abstract

The molecular mechanisms underlying doxorubicin-induced cardiotoxicity are still being investigated, but are known to involve oxidative stress, mitochondrial dysfunction, and the dysregulation of autophagy. The objective of the current study was to examine the protective role of metformin and its effect on autophagy in doxorubicin-induced cardiotoxicity. Sprague–Dawley rats were divided into four groups at random. The doxorubicin-treated group received doxorubicin (3 mg/kg every second day) intraperitoneally. The metformin-treated group received 250 mg/kg/day metformin via gavage. The doxorubicin + metformin-treated group received both at the above-mentioned doses. The control group received vehicle only. Following the two-week treatment, the hearts were isolated, and cardiac functions were registered. Serum levels of lactate dehydrogenase (LDH), creatine kinase iso-enzyme MB (CK-MB) enzyme, Troponin T, and cardiac malondialdehyde (MDA) were also measured. Heart tissue samples were histopathologically examined by using Masson’s trichrome staining and Western blot analysis was conducted for evaluating the expression level of AMP-activated protein kinase (AMPK) and autophagy-associated proteins beclin-1, LC3B-II, and p62, respectively. The results revealed that treatment with metformin conferred increased cardiac protection against the development of cardiotoxicity manifested by a significant decrease in serum Troponin T and cardiac MDA levels, and remarkable improvement in heart function in connection with histopathological features. Furthermore, by focusing on the contribution of autophagic proteins, it was found that metformin normalised autophagy, which may help cardiomyocytes survive doxorubicin-induced toxicity. These results promote the use of metformin, which would be a preferable drug for patients receiving doxorubicin. View Full-Text
Keywords: doxorubicin; metformin; AMPK; autophagy; cardiotoxicity; heart failure doxorubicin; metformin; AMPK; autophagy; cardiotoxicity; heart failure
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Zilinyi, R.; Czompa, A.; Czegledi, A.; Gajtko, A.; Pituk, D.; Lekli, I.; Tosaki, A. The Cardioprotective Effect of Metformin in Doxorubicin-Induced Cardiotoxicity: The Role of Autophagy. Molecules 2018, 23, 1184.

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