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Abstract
Doxorubicin is commonly used for the treatment of hematological and solid tumors. However, there are serious toxic effects on the cardiovascular system, which limits the application of the drug.
So, this study was designed to investigate the role of melatonin as a protective agent against doxorubicin-induced cardiomyopathy.
The experiment was conducted on seventy adult male albino rats with average weight 200 gm. Animals were kept in suitable conditions of temperature and illumination (12 hr light\ 12 hr dark cycle). They were fed standard laboratory chow and water ad libitum.
The animals were divided into 5 groups as follows:
Control groups which included G I (received no treatment), G II (received 10 mg \kg b.w. of melatonin) & G III (received 0.5 ml saline). Intoxicated groups (G IV) which is subdivided into: subgroup IVa: received a single i.p. injection of doxorubicin at a dose of 10 mg\kg b.w; subgroup IVb: received doxorubicin 3 mg\kg b.w. for 3 successive weeks. Protected groups (G V) which included: subgroup Va: received 10 mg\kg b.w. of melatonin subcutaneously before and after the single injection of doxorubicin; subgroup Vb: received 10 mg\kg b.w. of melatonin before and after every injection of doxorubicin for 3 successive weeks.
At the end of the experiment, the animals were sacrificed and their hearts were dissected. Specimens were prepared for histological and histochemical techniques. Blood samples were taken from the aorta for determination of serum lipids.
The cardiac muscle fibers of rats given a single dose of doxorubicin, showed some cells with pale acidophilic cytoplasm and intracytoplasmic vacuolization. Other cells showed deep homogenous acidophilic cytoplasm with pyknotic nuclei. Areas of ill defined cross striations and myofibrils were seen in Iron Hx and toludine blue stained sections. Minimal amount of collagen fibers were seen inbetween the cardiac muscle fibers in Mallory stained sections. Some cardiac muscle fibers showed depletion of PAS +ve material. Few red deposits could be detected in sections stained with Nile blue stain.
By electron microscope, myofilamentous disarrangement was evident. The mitochondria were disorganized, pleomorphic and showed variable degrees of damage.
More obvious findings were noticed in the cardiac muscles of rats which were given 3 doses of doxorubicin for 3 successive weeks, in the form of scattered focal areas of myocardial damage and fragmented fibers. Intracytoplasmic vacuolization was also present. Mononuclear cellular infiltration, intramyocardial hemorrhage and vascular congestion were noticed inbetween the cardiac muscle fibers. In semithin stained sections, sarcoplasmic vacuolization and pyknotic nuclei were seen. In Iron Hx stained sections, areas of disrupted myofibrils and disorganized striations could be seen. Marked increase in the amount of collagenous fibers between the cardiac muscle fibers was seen in Mallory stained sections. Myocytes of this group also showed marked reduction in the content of PAS +ve material. Multiple intracellular lipid DROPlets were seen in sections stained with Nile blue stain.
Immunohistochemical staining for Fas ligand showed positive reaction, while that of p53 was negative.
Electron microscopical examination revealed marked degeneration of the cardiac muscle fibers leaving empty areas. The mitochondria were disorganized, degenerated and pleomorphic. Giant mitochondria were also detected.
With concomitant administration of melatonin with the single dose of doxorubicin, most of the lesions were reduced. The cardiac myocytes appeared as short branching cylinders of uniform diameter. Semithin stained sections and Iron Hx stained sections showed cross striations and myofibrils. Minimal amount of collagenous fibers between the cardiac muscle fibers was seen in this group. Regarding PAS stained sections; there was reappearance of PAS +ve materials in most of the cardiac muscle fibers. No red deposits were seen in the cardiac muscle fibers in sections stained with Nile blue stain.
On electron microscopic examination, the myofilaments were more or less organized and the mitochondria regained their normal interposition between the myocytes with well defined oval or rounded contour and prominent cristae.
In animals received melatonin with the three doses of doxorubicin for three successive weeks, the cardiac muscle fibers showed vacuolated cytoplasm with pyknotic nuclei. Others showed deep homogenous acidophilic cytoplasm. In both Iron Hx and semithin stained sections, areas of ill defined cross striations and myofibrils were seen. In Mallory stained sections, collagenous fibers inbetween the cardiac muscle fibers slightly increased comparable to the control groups. Some of the cardiac myocytes still showed decreased content of PAS +ve materials. Few red deposits were seen in the cardiomyocytes in sections stained with Nile blue stain.
Ultrastructural examination was slightly similar to the control except for scattered foci of myofilamentous disarrangement and vacuolization. Some mitochondria appeared normal, while others appeared swollen with disrupted cristae.
Regarding the biochemical results, the doxorubicin-treated groups showed significant elevations of serum cholesterol, triglycerides and LDL cholesterol levels. whereas HDL cholesterol level was not significantly affected.
Melatonin administration was found to be effective in decreasing the high levels of serum cholesterol, triglycerides and LDL cholesterol.
from the results of the current study, it was concluded that doxorubicin had a toxic effect on the structure of cardiomyocytes and this toxicity increased with the increase in the dose and the duration of administration. Melatonin could be considered as a cardioprotective agent against doxorubicin-induced cardiotoxicity.
Therefore, it is advisable to test melatonin in clinical trials for prevention of heart damage associated with doxorubicin treatment in cancer patients.