STUDY THE SHORT TERM CHRONIC TOXICITY OF CYCLOSPORINE EXPOSURE ON TESTIS, HEART AND LUNGS AND THE POSSIBLE PROTECTIVE EFFECTS OF LARGININE IN ADULT ALBINO RATS

Objective: Cyclosporine A (CsA) is an immunosuppressive drug widely used after organ transplantation or in treatment of auto-immune diseases. However, several side effects are commonly associated with CsA long term intake. The Aim of the present study was to evaluate the sub-chronic toxicity (8 weeks) of CsA on testis, heart and lungs in adult male albino rats, and to determine the potential protective effect of amino acid L-arginine. Material and Methods: A total of 48 adult male albino rats divided into in to 4 groups. Group I (control group) which is subdivided into 3 groups each of 8 rats: Group I.a- negative control group each rat received only regular diet and water. Group I.b- positive control group: each rat received olive oil (0.5 cc) emulsion daily by oral gavage. Group I.c- positive control group: each rat received distilled water (0.5 cc) daily by oral gavage. Group II. Cyclosporine CsA group: (8 rats) each rat received Cyclosporine CsA 74 mg/kg (1\20 of LD50) in an olive oil emulsion (0.5 cc) daily by oral gavage .Group III. L-Arginine group: (8 rats) each rat received L-Arginine 300 mg/ kg daily by oral gavage .Group IV. Cyclosporine CsA plus L-Arginine group: (8 rats) each rat received 300 mg/ kg/day of L- Arginine by oral gavage a week before CsA treatment was initiated. The rats then received Cyclosporine CsA (74mg/kg in an olive oil emulsion) by oral gavage for 8 weeks. After the end of the study, blood samples were taken to measure serum testosterone levels. Testis, heart, and lungs were removed and subjected to histopathological study. Results: In CsA treated (group II), there was a significant decrease in the serum testosterone levels. Histopathological changes were in the form of (testis showed extensive degeneration of seminiferous tubules, necrosis and interstitial edema), (heart showed extensive connective tissue formation among myocardial fibers with disorganization of myocardial fibers confirmed by Masson’s Trichrome Stained sections revealing extensive fibrosis( and (lungs showed large area of acute bronchopneumonia, many alveolar walls are covered by fibrin exudates and inflammatory cellular infiltrate). While Cyclosporine CsA plus L-Arginine group (group IV) revealed partial improvement in the previous histopathological changes. The heart, showed mild myocardial disorganization and sparse connective tissue among myocardial fibers. The lung showed edematous thickening of the alveolar walls and sparse inflammatory cellular infiltrate and the testis showed that most of seminiferous tubules retain its normal structure, few show degeneration and necrosis. Conclusion: From the previous results, it can be concluded that CsA induced toxic effects in the testis as evidenced by biochemical and histopathological changes. Also,Heart and lungs showed histopathological damage. Pre-treatment with L-Arginine group (IV) reduced the subsequent CsA injury in testis, heart and lungs.