Protective Effect And Mechanism Of Garlic Polysaccharide On Adriamycin-induced Cardiotoxicity In Experimental Animals

AIM: Adriamycin (ADR), an anthracycline antibiotic, is widely used in the treatment of a variety of human malignant tumors, including breast cancer, small cell carcinoma of the lung and acute leukemia's. Like most of the anticancer drugs, ADR causes various toxic effects, such as the dose-dependent cardiotoxicity resulting in acute or chronic heart failure. Thus, seeking secure and efficacious anti-ADR injury drugs, especially from our abundant herbal resources, is a significant topic. On account of the obvious protective effects of Garlic Polysaccharide (GP) on coxsackie B₃ viral myocarditis in mice, we studied the protective effects and mechanisms of GP on ADR-induced cardiotoxicity at functional, biochemical, morphological and molecular levels in the model of ADR-induced myocardium injury in vivo and in vitro.METHOD: ADR was injected intraperitoneally to induce myocardium injury model in mice. The activities of several serum and heart tissue enzymes were measured. The apoptotic cardiomyocytes were shown by in situ end labeling method. Bcl-2 and Bax gene expressions were evaluated by immunocytochemistry. With scanning electron microscope, the cardiac ultrastructural changes in damaged myocardium were examined. The ADR injury model in vitro was established in primary culture neonatal Sprague Dawley rat cardiac myocyte, the activities of several enzymes in culture medium and cells were measured. Using MTT assay, the TCD₀ and TCD₅₀ of GP were determined. Flow cytometry was used to detect the apoptotic cardiac myocytes.RESULTS: ADR (3 mg·kg^-1 ip, qod × 7) induced severe myocardial damages with the increased activities of creatine kinase (CK), lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) and inducible nitric oxide synthase (iNOS) in blood serum (P < 0.01). In myocardial homogenate, ADR increased the malondialdehyde (MDA) content but decreased the superoxide dismutase (SOD) activity (P < 0.01).Meantime, ADR increased the number of apoptotic cardiomyocytes and the gene expressions of Bax and Bcl-2. It also caused mitochondrion edema at ultrastructural level. GP (0.75-3.0 g-kg"1 ig, qdxl5) relieved these damages in several ways. It decreased the activities of serum CK, LDH, GOT and iNOS. Besides, it increased SOD activity and depressed MDA content in the dose-dependent manner. Furthermore, the gene expression of Bax was decreased sigmficantly while the protein expression ratio of Bcl-2/Bax was increased. Especially, the high dose of GP represented the maximal effectiveness. In addition, the changes of myocardial pathological and ultrastructural damages were improved by GP. In vitro study, ADR increased the supernant CK, LDH, GOT activities (P < 0.01). In the cardiac cell, the MDA content was augmented, but SOD activity was decreased (P < 0.01). Moreover, GP (25-100 ug-ml'1) decreased the activities of CK, LDH and GOT, increased SOD activity and depressed MDA content in a concentration-dependent manner. The outcomes corresponded to the in vivo study.CONCLUSION: These observations highlight the antioxidative property of GP and its cytoprotective action against ADR-induced cardiotoxity.