Impact of trimetazidine on doxorubicin-induced acute cardiotoxicity in mice: a biochemical and electron microscopic study

ABSTRACT

Doxorubicin [Dox] is an effective broadly used anti-tumor drug. However, its therapeutic success is limited due to the development of acute and chronic cardiotoxicity. Therefore, the purpose of this study was to evaluate the effect of trimetazidine [TMZ] on Dox-induced acute cardiotoxicity in mice using biochemical and electron microscopic approaches. Thirty male mice weighing 30 gm +/- 5gm were used. They were equally divided into 3 groups. Group I represented the control group. Animals of group II, were intraperitoneally [IP] injected with a single dose of Dox [15mg/kg]. In group III, the mice were IP injected with TMZ [2.5mg/kg/d] for 5 days before single injection of the same dose of Dox. Thirty hours after Dox injection, animals were anaesthetized. Blood samples were obtained and serum was separated for measurement of cardiotoxicity indices [creatine phosphokinase isoenzyme [CK-MB], lactate dehydrogenase [LDH] and aspartate aminotransferase [AST]]. Hearts were dissected and each was divided into two halves, one half was used for measurement of myocardial oxidative stress [thiobarbituric acid reactive substance [TBARs], nitrate /nitrite [NOx]] and myocardial antioxidant activity [glutathione [GSH]] level. The other half was processed for electron microscopic study [EM]. In group II, there were significant increase in CK-MB, LDH, AST, TBARs and NOx and a significant decrease in GSH. Electron microscopic examination revealed severe toxic effect on the cardiac muscle in the form of myofibrillar lysis, cytoplasmic vacuoles, oedema, dilatation of sarcoplasmic reticulum, mitochondrial damage, increased number of 2ry lysosomes, widening of the junctions forming the intercalated discs and mononuclear cellular infiltrate between the disorganized cardiac myocytes, whereas group III revealed marked improvement in all biochemical parameters and EM study revealed almost a similar myocardial histological profile to the control group. In conclusion, TMZ ameliorates Dox-induced acute cardiotoxicity in mice by reduction of myocardial oxidative stress and preservation of endogenous antioxidant activity