Protective Effect Of Curcumin On Doxorubicin Cardiotoxic Mice

Objective:In this study,we established doxorubicin(DOX)induced cardiotoxicity mouse model,and intervened with curcumin(Cur)at different concentrations to study the protective effect of Cur on DOX-induced cardiotoxicity and its possible mechanism,so as to provide experimental and theoretical basis for the prevention and treatment of DOX-induced cardiotoxicity.Methods:120 male Kunming mice were randomly divided into six groups:(1)control group(Con group,n=20);(2)model group(DOX group,n=20);(3)low dose Cur treatment group(DOX-Cur 100 mg·kg^-1group,n=20);(4)medium dose Cur treatment group(DOX-Cur 200 mg·kg^-1group,n=20);(5)high dose Cur treatment group(DOX-Cur400 mg·kg^-1group,n=20);(6)high dose Cur control group(Con-Cur 400 mg·kg^-1group,n=20).Mice were intraperitoneally injected with 3 mg·kg^-1DOX,once every other day,with a cumulative dose of 24 mg·kg^-1,to establish DOX cardiotoxicity mice model.Different doses of Cur(mixed with 0.5%sodium carboxymethylcellulose)were given by gavage daily.On the 17th day,the mice were anesthetized and killed,and the hearts were separated and weighed.The heart weight/body weight(HW/BW)of the mice was measured.The levels of creatine kinase(CK),aspartate aminotransferase(AST),lactate dehydrogenase(LDH)in serum and the levels of malondialdehyde(MDA),superoxide dismutase(SOD)in heart homogenate were detected by biochemical kit.The changes of myocardial microstructure were observed by HE staining,The changes of myocardial ultrastructure were observed by transmission electron microscope.The expression levels of apoptosis related proteins Bax,Bcl-2,pyroptosis associated proteins NLRP3,Caspase-1,IL-1?,IL-18,autophagy related proteins Beclin-1,LC3B and Akt/mTOR signaling pathway proteins were determined by Western blot.Results:Compared with the Con group,the BW,HW and HW/BW ratio of DOX group were significantly decreased(P<0.05),the activities of CK,AST and LDH in serum were significantly increased(P<0.05),the content of MDA in heart homogenate was significantly increased(P<0.05),the myocardial fibers were dissolved,broken and vacuolated,the mitochondria were significantly swelled,and the number of double membrane autophagosomes significantly increased.In addition,the expression level of apoptosis related protein Bax and the ratio of Bax/Bcl-2 in the myocardial tissue of the DOX group were significantly increased(P<0.05),the expression levels of NLRP3,Caspase-1,IL-1?and IL-18 were significantly increased(P<0.05),the expression level of autophagy related protein Beclin-1 and LC3B-II/I ratio were significantly increased(P<0.05),while the ratio of p-Akt/Akt and the ratio of p-mTOR/mTOR were significantly decreased(P<0.05).Cur could reverse the above changes induced by DOX,such as increasing the HW and HW/BW ratio,decreasing the activities of CK,AST and LDH in serum and the content of MDA in heart homogenate,decreasing the protein expression levels of Bax,NLRP3,Caspase-1,IL-18 and Beclin-1,as well as the ratio of Bax/Bcl-2 and LC3B-II/I,and increasing the expression levels of Bcl-2,as well as the ratio of p-Akt/Akt and the ratio of p-mTOR/mTOR,especially Cur 100 mg·kg^-1treatment group had significant effect(P<0.05).At the same time,the results of light and electron microscopy showed that Cur could significantly improve the pathological changes of myocardial structure and reduce the number of autophagosomes.Conclusion:Cur can play a protective role in DOX-induced cardiactoxicity in mice by inhibiting oxidative stress,apoptosis,pyroptosis and autophagy.The mechanism may be related to activation of Akt/mTOR signaling pathway.