Protective Action of a Modified Galanin Fragment in Rats with Doxorubicin-Induced Heart Failure

The clinical application of the anticancer agent doxorubicin (Dox) is limited due to its cardiotoxic effect. Using the method of automated solid-phase peptide synthesis, we obtained a synthetic agonist of galanin receptors GalR1-3 [βAla14, His15]-galanin (2-15) (G), exhibiting cardioprotective properties. It was purified by high performance liquid chromatography (HPLC). The homogeneity and structure of the peptide were confirmed by HPLC, 1H-NMR spectroscopy and mass spectrometry. The aim of this study was to investigate the effect of G on metabolism and cardiac function of rats with chronic heart failure (CHF) caused by Dox. Experiments were performed using male Wistar rats weighing 280–300 g. The control group of animals (C) was intraperitoneally treated with saline for 8 weeks; the doxorubicin group (D) of rats was intraperitoneally treated with Doх; the group Doх + peptide G (D + G) of rats received intraperitoneal injections of Doх and subcutaneously injections of peptide G; the peptide G group (G) was subcutaneously treated with G. At the beginning and at the end of the study, the concentration of thiobarbituric acid reactive substances (TBARS) and the activity of creatine kinase-MB (CK-MB) were determined in blood plasma; the animals were weighed, and cardiac function was assessed using echocardiography. At the end of the experiments, the hearts were used for determination of metabolites and assessment of oxidative phosphorylation in mitochondria. After the 8-week treatment, animals of group D were characterized by severe heart failure, the lack of weight gain and an increase in plasma TBARS concentration and CK-MB activity. These impairments were accompanied by a decrease in the content of myocardial high-energy phosphates, a reduction in mitochondrial respiratory acid parameters, accumulation of lactate and glucose in the heart, and altered metabolism of alanine, glutamic acid and aspartic acid. Coadministration of G and Dox prevented the increase in plasma CK-MB activity and significantly reduced the plasma TBARS concentration. At the end of the experiments, animals of group D + G had higher myocardial energy state and the respiratory control index of mitochondria than animals of group D; there was a decrease in anaerobic glycolysis and lack of changes in the amino acid content compared to the control. The peptide G significantly improved the cardiac function parameters and caused weight gain in animals of group D + G in comparison with these parameters in group D. The obtained results demonstrate the ability of a novel agonist of galanin receptors GalR1-3 to attenuate Dox-induced cardiotoxicity.