الفهرس 
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Abstract
Cyclosporine A (CsA) is a potent, commonly used immunosuppressant with selective helper T-lymphocyte action that is typically used to prevent rejection in organ transplantation and in the treatment of autoimmune diseases such as immune mediated hemolytic anemia, atopic dermatitis, and sebaceous adenitis. It is a well-known nephrotoxin which can cause irreversible injuries to the renal tubules; however, the adverse effect of CsA on body organs other than the kidney is poorly studied and need to be further investigated.
In the current study, a total number of 60 white male albino rats of 100-120 g body weight were used to investigate the possible adverse effects of different doses of CsA on different organs in male albino rats, and also to study the possible protective effects of vitamin E on this toxicity.
Rats were randomly divided into five equal groups (12 rats of each) and received treatments for 21 days as follow: Group I: Rats were intubated with Cyclosporine A using stomach tube at a dose of 50mg/kg B.wt. Group II: rats were intubated with Cyclosporine A at a dose of 75mg/kg B.wt. Group III: Rats were intubated at a dose of 50mg/kg B.wt. concurrently with oral dosing of vitamin E at a dose of 100mg /kg B.wt. Group IV: Rats receive only vitamin E at dose of 100mg /kg B.wt. Group V: served as control.
Depression, loss of appetite and subsequent significant loss of body weight were the main clinical signs in the CsA-treated groups with high mortalities percent restricted to these three groups (33.3, 58.3, 58.3; respectively).
Postmortem examination of rats in groups (I, II, III) revealed enlarged pale liver suggesting different grades of fatty change and occasional mottled appearance suggesting focal necrosis, with pale kidneys showing cortical atrophy and no distinct borders between medulla and cortex.
Microscopically, the detectable lesions of rats receiving CsA either alone or in combination with vitamin E were of the same pattern considering differences in severity and distribution. Concerning hepatic lesions, they were interpreted as centrilobular and midzonal coagulative necrosis with multifocal pleocellular mononuclear aggregates infiltrated the necrotic areas, acute cellular swelling of hyDROPic and lipid types, and hepatocellular apoptosis which confirmed by mean of TUNEL assay.
Renal lesions in the CsA-treated groups were in form of acute tubulonephrosis and tubular necrosis in approximately 10-20% of available proximal convoluted tubules with markedly attenuated tubular epithelium, sparse basophilic cytoplasm, pyknotic or karyorrhectic nuclei and interstitial inflammatory aggregates around the necrotic tubules. The non-necrotic cortical tubules were mildly swollen and had a granular or foamy eosinophilic cytoplasm and their lumens contained eosinophilic homogenous debris. Moreover, few glomeruli particularly those neighboring the affected areas were atrophied or sclerotic beside congestion of intertubular blood capillaries and glomerular tufts. Multifocal infarcts at the subcortical and subcapsular areas, regenerated tubules and early mild fibrosis appeared after 21 days of experiment.
Renal and hepatic lesional score were measured for groups (I and III) receiving double therapeutic dose of CsA either with or without vitamin E and suggested that vitamin E cause mild decrease in the severity and distribution of reported hepatic lesions from 63 to 56 and renal lesions from 30 to 22 after 21 days of experiment.
Concerning the statistical analysis of kidney and liver function, group I showed significant increase in ALT and AST levels over group III after 10 and 21 day of experiment which may suggests the therapeutic role of vitamin E in improvement of liver function. While, the recorded levels of urea and creatinine in the two mentioned groups were significantly increased than that of control one but not significantly differ from each other.
In conclusion, this study confirmed that CsA should not be only considered as a nephrotoxin but also as a powerful hepatotoxin and part of this toxicity is at least caused by the proapoptotic effect of CsA in liver. Also, the administration of Vit E. has a minimal protective effect on this toxicity at the doses used in this study.