الفهرس 
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Abstract
Solid organ transplantation has been extensively used as treatment for end-stage organ failure in the last 20 years. Begining with kidney transplantation but later including liver, heart and lung, this technique has become a valuable treatment for lethal diseases. Cyclosporin A (CsA) has revolutionized post-transplantation immunosuppressive therapy, due to its potent selective immunological properties, and also has potential advantages over conventional treatments in the area of autoimmune diseases. CsA also is the first choice immuno- suppressant used for prevention of allograft rejection. However CsA therapy is associated with nephrotoxicity, hepatotoxicity, testicular and spermatozoa toxicity. There are several hypotheses to explain the mechanism of cyclosporine A-induced adverse effects, including the formation of free oxygen radicals and lipid peroxidation.
The practice of preventing and/ or reversing the damaging effects of immunosuppressive drugs is an effective mean for improving human health. The target of much research has been the discovery of natural compounds that are used in the preventing/ or the treatment of the side effects induced by immunosuppressive drugs.
The target of the present study was to investigate the protective effect of ellagic acid (EA) on CsA induced biochemical and oxidative stress changes, testicular and spermatozoa toxicity, hepatotoxicity, nephrotoxicity and finally genotoxicity in male albino rats (Rattus norvegicus). Biochemical changes were evaluated by measuring liver functions (ALT and AST parameters) and kidney functions (serum urea and creatinine concentration), oxidative stress changes by measuring lipid peroxidation, catalase, glutathione and finally peroxidas activity, testicular and spermatozoa toxicity, hepatotoxicity and nephrotoxicity were evaluated histochemically, histopathologically and ultrastructuraly by light and electron microscopy and finally genotoxicity and cytotoxicty were evaluated by bone marrow chromosomal aberration assay and mitotic index respectively.
72 experimental rats were organized into 6 groups including 12 animals per each for 30 days. The animals of group one served as normal control group receiving tap water. The animals of group two were received subcutaneous injection of slightly alkaline solution once/ day, while the animals of group three were received olive oil through gastric intubation. The animals of group four were received subcutaneous injection of EA (10 mg/kg b. wt.). The Animals of group five were orally administered CsA (15mg/kg b. wt.) dissolved in 1ml olive oil by gastric tube. Finally the animals of group six were subcutaneous injected with EA (as in G4) in parallel to orally administration of CsA (as in G5).
The animals which received CsA alone showed changes in biochemical, histological, histochemical, ultrastructural and genetical manifestation. First it induced a marked decrease in body weight gain at (p < 0.001) and on the other hand it induced an increase in liver marker enzymes (ALT and AST) and kidney function indicators (serum urea concentration and creatinine level) at (p < 0.001). Finally, CsA resuled in an increase in lipid peroxidation and a decrease in glutathione level, catalase and peroxidase activity of testis, liver and kidney tissues.
Histopathological assessment of the testis, after administration of cyclosporine A, showed that the seminiferous tubules are irregular amd variable sizes. Atrophy and focal necrosis in germinal cells, interstitial oedema and capillary congestion were also appeared. In addition to pyknotic nuclei, vacuolation and congestion in intercellular space are also seen. Testis tissues of CsA treated rats showed faint PAS positive reaction and depletion of protein staining reaction when compared with control group. Ultrastructural examination of the testis tissues of CsA administrated rats showed A thick and a folded basement membrane, the sertoli cells showed numerous cytoplasmic vacuoles and primary spermatocytes contain damaged mitochondria. In addition, the late spermatids exhibited irregular acrosomes and nucleus were deformed.
The microscopic examination of the liver tissues of CsA treated rats showed inflammatory cells infilterations, hydropic degenerated hypatocytes highly dilated central veins and newly formed bile ductules. Also, liver tissues of CsA treated rats showed faint PAS positive reaction and depletion of protein staining reaction when compared with control group. Electron microscope examination showed nearly complete disintegration of most cellular contents. Damaged mitochondria with dissolution in their cristae and deformed nuclear membrane. In addition, a clumping of cell organelles, whorly appeared structures and vacuolated cytoplasm were observed.
Finally, the microscopic examination of the kidney cortex tissues of CsA treated rats showed infiltration of inflammatory cells, atrophied glomerular tuft, some cells appeared with vacuolated cytoplasm and other with pyknotic nuclei and hemorrhage. In addition to appearing of muscle fibres which indicated hydrobic degeneration. Also, medulla region appeared with tubular calcifications or cast in the tubules, infiltration of inflammatory cells and damaged collecting tubules. CsA treated rats showed strong PAS positive reaction and depletion of protein staining reaction when compared with control group. Renal corpuscles showed marked degeneration of almost structures of the glomeruli, including podocytes with electron dense nuclei, effacement of the foot processes, damaged fenestrated endothelium of the capillary and focal thickening of the glomerular basement membranes. The proximal tubules showed irregular basal mitochondrial, multiple cytoplasmic vacuoles and electron-dense bodies. Also, damaged nuclei and sparse short microvilli were observed.
Genetically CsA induced a high frequency of chromosomal aberrations in bone marrow cells, while the mitotic index was significantly decreased indicating bone marrow cytotoxicity.
All the biochemical changes, histological and ultrastructural alteration side effects in testicular, hepatic and renal tissues were greatly ablated using ellagic acid (EA) with significant reduction in chromosomal aberrations and elevation of mitotic index (p < 0.01). EA dose at 10 mg/ kg most potent in exerting ameliorative effects. In addition to the suppressive effects of EA exposed high effect nearly similar to the control group.
In conclusion, cyclosporine A (CsA) has adverse effects on human health. The results demonstrated that the administration of CsA to rats at a dose of 15 mg/kg daily for 30 days is capable of inducing marked biochemical, histopathological and ultrastructural alterations in testis, liver and kidney tissues in addition to observable chromosomal aberrations and alterations in mitotic index. The use of EA in concomitant with CsA was ascertained to alleviate the harmful effects of CsA in the mentioned parameters.