The Potential protective role of astaxanthin on doxorubicin-induced cardiac toxicity in rats

Abstract Background and Aim of Work Doxorubicin (DOX) is one of the most commonly used effective anticancer drugs, through its inhibition of topoisomerase II, DNA replication and repair. In addition, DOX leads to generation of semiquinone free radicals and oxygen free radicals which attack DNA and oxidize DNA bases. However, the clinical use of doxorubicin is limited by its adverse effects such as cardiotoxicity, which is acute and occurs within 2-3 days of its administration. Recently, the potential health benefits of Astaxanthin were investigated, however, the protective effect of astaxanthin supplementation on cardiac dysfunction induced by Doxorubicin is not clearly investigated. The aim of the present study is directed to investigate the possible role of astaxanthin (xanthophyll carotenoid) in protection against DOX- induced cardiac toxicity, and to elucidate the underlying mechanism(s). Materials and Methods Animals used were 47 adult male albino rats, which were randomly allocated into four groups. Control group(C): received 0.1ml/100gm BW i.p. saline injections for 7 successive days. DOX-treated group: received 0.1ml/100gm BW i.p. saline injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. ATX-treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days. ATX+DOX treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. At the end of the study, the overnight fasted rats were subjected to final arterial blood pressure measurement. Rats were then weighed and anaesthetized with 40 mg/kg B.W i.p. thiopental sodium. Then, ECG was recorded, blood samples were collected from abdominal aorta and centrifuged. The resulting plasma was used for measurement of plasma cardiac Troponin I (cTnI) and plasma Cytochrome C. The heart was subjected to In vitro study of isolated hearts perfused in langendorff preparation. Hearts and ventricles were weighed. The left ventricle was then stored at -80οC for later determination of cardiac tissue iron. Statistical Analysis was made using 1-way ANOVA for difference between means of different groups. Ethics Committee The study protocol was approved by the Research Ethical Committee of Faculty o fMedicine Ain Shams University (Reference No. FWA00017585). Results The systolic blood pressure was increased significantly in the DOX treated group compared to the control group. All of the systolic, diastolic and mean arterial blood pressures were significantly decreased in the ATX +DOX treated group compared to the DOX treated group. Heart rate was significantly increased in the ATX +DOX treated group compared to the control group, and compared to the DOX treated group. PT and PT/LVW were significantly increased in the ATX +DOX group compared to both of the DOX group and the control group. In addition, PT and PT/LVW were significantly increased in the ATX-treated group compared to the DOX group. The TPT was prolonged in the DOX group compared to the control group and this prolongation was statistically significant in pre-ischemia and 5 minutes after reperfusion of the isolated hearts, and was significantly shortened in the ATX-treated group and ATX +DOX group compared to the DOX. Also, TPT was significantly shortened in the ATX-treated and in the in the ATX +DOX groups compared to the control group. HRT was significantly prolonged in the DOX group compared to the control group. However, HRT was significantly shortened in the ATX-treated and ATX +DOX groups compared to the DOX group, and in the ATX +DOX group compared to the control group. The MFR and MFR/LVW were significantly decreased in the DOX group compared to the control group. However, the MFR was significantly increased in each of the ATX-treated group and ATX +DOX group when each was compared to the DOX group. Moreover, MFR was significantly increased in the ATX +DOX group compared to the control group. Each of plasma cardiac Troponin, plasma Cytochrome C and Cardiac Tissue Iron were significantly increased in the DOX group compared to the control group, and all were significantly decreased in the ATX-treated group when compared to DOX group, and in the ATX +DOX group when compared to the DOX group. No significant changes were detected in body weight, heart weights and ECG parameters between the different studied groups. Conclusion Doxorubicin produces acute cardiotoxic effects and impairs systolic and diastolic cardiac functions, which is due to increased oxidative stress, mitochondrial instability and iron accumulation in the cardiac tissue. Astaxanthin exerts a major cardioprotective activities against DOXinduced cardiotoxicity, probably due to its major antioxidant and iron chelation properties.