Prevention Effects of Schisandrin B on Cardiotoxicity Induced by Anthracyclines in Rabbit Model

Background: Dutriomycin, which doxorubicin(DOX) act as a representative among them, has been extensively administrated to treat many kinds of malignant tumours, such as leukemia, lymphoma, breast cancer, and so on. However, its application was confined for its obvious cardiotoxicity in some degree. The mechanism of which cardiotoxicity result from dutriomycin is usually attributed to too much product of free radical. The protective effect of dexrazoxane(DEX) on cardiotoxicity induced by dutriomycin has been proved by animal and clinical researches and its price is relatively expensive. Schisandrin B(SchB), one of the chinese medicine, have showed a significant effect on removing oxygen free radical and hydroxy radical and it has almost no toxicity and adverse reaction. Also, it is easy to procure.

Objective: This study is to determine and compare the protective effects of SchB and DEX on the cardiotoxicity of rabbit model induced by doxorubicin.

Methods: 46 New Zealand White rabbits were divided into three groups:

1. DOX group(n=14), DOX was administered intravenously with 3mg/kg for each rabbit, once a week;

2. DOX+DEX group(n=17), DOX was also administered intravenously with 3mg/kg for each rabbit, once a week and DEX was given by intra-abdominal cavity with 60mg/kg in 30 minute before the administration of DOX for each rabbit, once a week (week1 `week3) and which was administered intravenously with the same dose by the same way from week 4 to week 12. The total cumulative dose of DEX was 600mg/kg;

3. DOX+SchB group (n=15), DOX was still administered intravenously with 3mg/kg for each rabbit, once a week and SchB was given intravenously with 10.5mg/kg, twice a week.

The cumulative dose of SchB was 210mg/kg for each one. The correlated indexes of heart damage induced by DOX and protective action created by DEX and SchB were determined respectively. Quantitative detections of superoxide-dismutase(SOD), malondialdehyde(MDA), cardiac troponin I(cTnI) and brain/B-type natriuretic peptide (BNP) were performed before experiment, at 4 weekend and at 8 weekend after study, as well as at the end of whole research. Echocardiography was performed to evaluate the changes of heart function for each rabbit in three groups before the first administration, at 4 weekend and 8 weekend after study and at the endpoint of the experiment respectively. The rabbits were killed at the endpoint of this study, and the pathological changes of their cardiac tissues were be observed by microscope under the condition of H.E stain and the apoptosis of myocardial cells were detected by TUNEL method.

Results: The levels of MDA, cTnI and BNP are increased, and the activity of SOD, left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS) are decreased in the DOX group(P<0.05). Compared with DOX group, the levels of MDA, cTnI and BNP are decreased, and LVEF and LVFS are increased in the DOX+DEX group(P<0.05). The level of MDA is also decreased(P<0.05), and the activity of SOD, LVEF and LVFS are increased(P<0.05) in the DOX + SchB group compared with the DOX group. In the DOX+DEX group, the level of BNP is lower than DOX+SchB group. Compared with the DOX group, the pathological change of myocardium and the apoptotic index of myocardial cells are significantly reduced in the DOX+DEX group and DOX+SchB group.

Conclusions: SchB and DEX has both protective effect on cardiotoxicity induced by DOX, and DEX is prior to SchB in the protective effect. The mechanisms of SchB may depends on the effects on scavenging oxygen free radials, decreasing productions of lipid peroxidation, which is different from dexrazoxane.