Effects of Melatonin and Adrenomedullin in Reducing the Cardiotoxic Effects of Doxorubicin in Rats

Abstract

The main disadvantage of doxorubicin (DOX) is that it has cardiotoxic side effects. Our aim is to evaluate the cardioprotective effects of adrenomedullin (ADM) and to compare these effects with melatonin (MEL), it's cardioprotective effects are well known. Rats were divided into four groups: Control group (0.9% NaCl solution, intravenously), Doxorubicin group (45 mg/kg DOX, intravenously), Doxorubicin + Melatonin group (DOX + MEL, 10 mg/kg melatonin, intraperitoneally), Doxorubicin + Adrenomedullin group (DOX + ADM, 12 µg/kg adrenomedullin, intraperitoneally). A single dose of DOX was injected to the experimental groups on day 5, and a single dose of 0.9% NaCl solution was injected to the control group through the tail vein. The animals were anesthetized and ECG recordings were obtained on day 8. For the purpose of biochemical and histological analysis, cardiac tissue biopsy was obtained after ECG recordings. Compared to the control group, the DOX group had significantly increased duration of QRS complex, PR interval, QT interval and QTc interval. QRS complex, QT interval and QTc interval were prolonged with the administration of DOX and shortened with the administration of ADM. MEL weakened the toxic effects of DOX on the cardiac tissue and it is shown histologically. DOX increased interleukins (IL-1α, IL-6, IL-18), tumor necrosis factor-α (TNF-α), hypoxia-inducible factor 1-alpha (HIF-1α), malondialdehyde (MDA), nitric oxide (NO), creatine kinase myocardial band (CK-MB), and total oxidant status (TOS) levels in cardiac tissue, while reducing total antioxidant status (TAS), superoxide dismutase (SOD) and catalase (CAT) levels. MEL administration decreased the levels of CK-MB, MDA, IL-1α, IL-6, IL-18, NO, and TNF-α, whereas ADM only decreased IL-1α, IL-18, MDA and TNF-α levels. In summary, these results show that DOX has toxic effects on rat cardiac tissue which is documented histologically, electrocardiographically and biochemically. MEL alleviated histological damage and showed improvement on the several biochemical parameters of cardiac tissue. ADM brought several electrocardiographic and biochemical parameters closer to normal values.

Keywords: Adrenomedullin; Antioxidants; Cardiotoxicity; Doxorubicin; ECG; Melatonin.