ABSTRACT
Doxorubicin is one of the first anthracyclines in clinical use and has a broad anti-tumor spectrum. With the increasing use of anthracycline antibiotic, acute and cumulative dose-related cardiotoxicity have been recognized. This work was undertaken with the aim of studying the histological, Ultrastructural and immunohistochemical changes in the myocardium of albino rats following doxorubicin administration and the possible protective role of an antioxidant [probucol]. Sixty adult albino rats of both sexes weighing 200 - 250 gms, were used in this study. They were divided into four groups: a control group [group I] composed of 30 rats and three treated groups [10 rats for each]. Probucol treated group [group II], were injected intraperitoneally [IP] with probucol in a dose of 10 mg / kg b. w every other day for four weeks. Doxorubicin treated group [group III], were injected [IP] with doxorubicin in a dose of 2.5 mg / kg b. w. every other day for two weeks. Probucol and doxorubicin treated group [group IV], were injected [IP] with probucol for two weeks followed by probucl plus doxorubicin for another two weeks with the same doses and ways mentioned before. The control animals were divided into three subgroups [10 rats for each], [group la], were injected [IP] with 1ml corn oil [solvent for probucol]. [group Ib] were injected [IP] with 1ml physiological saline [solvent for doxorubicin]. [group Ic] were injected [IP] with 1ml physiological saline and 1 ml corn oil by the same ways and durations mentioned before with treated animals. Heart specimens were taken two and four weeks after the last injection and processed for histological, Ultrastructural and immunohistochemical studies. Light microscopic studies revealed many degenerative changes that were time-dependent varying from vacuolation to myocytolysis and loss of myofibrils. Evidences of apoptosis were detected in the form of cytoplasmic eosinophilia and the nuclei varying from peripheral margination of chromatin up to pyknosis, confirmed immunohistochemically with positive reaction for caspase-3 activity that was increased in a time-dependent manner to reach up to four times of the control level four weeks after doxorubicin treatment, as detected by image analysis. Ultrastructural examination showed extensive degeneration of the muscle fibers with marked loss and even complete disappearance of myofibrils, there was dilatation of smooth endoplasmic reticulum, increased amount of glycogen granules and mitochondriosis, with degeneration and moth-eaten appearance of many mitochondria. The nucleus appeared hyperchromatic with peripherally clumped chromatin. The above mentioned toxic effects of doxorubicin on the myocardium were markedly attenuated by probucol administration before and in combination with doxorubicin injections. From this study, it was concluded that, probucol markedly attenuated doxorubicin induced cardiomyopathic changes which is time- dependent