Cyclosporine A versus cyclosporine G: a comparative study of survival, hepatotoxicity, nephrotoxicity, and splenic atrophy in BALB/c mice

Abstract

Abstract. Our group has previously shown that cyclosporine A (CSA) but not cyclosporine G (CSG) causes splenic atrophy in a BALB/c mouse model. We have now extended our studies to observations of the effect of the two drugs on other parenchymal organs and on the nervous system. Groups of mice (N= 30) were given 150 mg/kg per day of either CSA or CSG and were compared to two control groups. Absorption of the drugs was similar in the two groups, although CSG blood levels were slightly higher. Animals treated with CSA, but not CSG, lost up to 50% of body weight over a 3-week period. Overall mortality was much higher in the CSA group. Blood urea levels were significantly higher in both treatment groups than in controls and were significantly higher in the CSA than in the CSG group. CSA-treated animals showed marked histological changes in their kidneys, the most prominent of which was proximal tubular vacuolation. Both drugs showed some hepatotoxicity, both histologically and biochemically; the histological changes were more marked in the CSA group. There was no pancreatic toxicity at this dose, either histologically or in terms of blood-sugar concentrations. Mice treated with CSA, but not with CSG, showed marked behavioral changes, including hyperactivity and irritability. The most intriguing observation was the effect of CSA, but not CSG, on the spleen. There was atrophy of lymphoid tissue in both the B and the T cell areas, although the most prominent change was in the periarterial lymphatic sheaths. These changes may be of significance in the long-term maintenance of immunosuppression and graft acceptance. CSG appears, therefore, to be significantly less toxic overall in this model than CSA and warrants further study, both experimentally and clinically.