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

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

Light and electron microscopic study of the effect of sodium valproate on the quadriceps femoris muscle of rat and the possible protective role of L-carnitine

Sodium valproate [VPA] is a broad spectrum antiepileptic drug. Patients especially children who receive VPA for a long time present with myalgia and exercise intolerance. The aim of the present study was to elicit the effect of VPA on the skeletal muscle and the possible protective role of L-carnitine. Fifty male albino rats were used in this study. The animals were divided into two groups: group A [control group] and group B [experimental group] which was subdivided into 4 subgroups: group B1 and B2 received VPA only [50 mg/kg/day], for 1 and 2 months respectively. Group B3 and B4 received VPA and L-carnitine [300 mg/kg/day] for 1 and 2 months respectively. At the end of the experiment blood samples were collected to evaluate serum VPA levels. Quadriceps femoris muscles [QFM] were dissected and processed for light and electron microscopic [EM] study. In group B1, some QFM fibers showed loss of their striation or longitudinally splitted. Some intermediate muscle fibers appeared to be deficient in succinic dehydrogenase enzyme[S-DH] activity. EM study revealed many lipid droplets and enlarged degenerated mitochondria in-between the myofibrils. The mean serum VPA level was 101.6 +/- 7.88 micro g/ml. In group B2 the majority of muscle fibers were degenerated with mononuclear cellular infiltration and marked decrease in S-DH activity in all types of muscle fibers. Disorganized myofibrils, megamitochondria and lysosomes were seen. The lipid and glycogen granules were increased. There was a non significant increase in the mean serum VPA level [105.01 +/- 6.34 micro g/ml]. On the other hand, there was a highly significant decrease in the mean serum VPA level in group B3 [85.39 +/- 5.93 micro g/ml] and B4 [86.23 +/- 8.39 micro g/ml]. No histological changes were observed in these two groups except that some mitochondria were enlarged in group B4. In conclusion, the use of L-carnitine has a great role in protection against VPA-induced myopathy and it should be prescribed for all patients treated with VPA for long time