Long-term cyclosporine treatment: Evaluation of serum biochemical parameters and histopathological alterations in Wistar rats

Abstract

The immunosuppressant agent cyclosporine (CsA) is currently used in transplanted patients and in the therapy of autoimmune disorders. CsA treatment has significant acute and chronic side effects on the liver and kidney. However, in the clinical setting, it is difficult to distinguish a direct effect of CsA treatment from other confounding variables, such as allograft rejection and effects due to other drug therapies. In the present study, we assessed for direct associations between CsA immunosuppressive therapy and cytokines levels, kidney and liver functionality, as well as lung histopathological status in rats submitted to chronic CsA treatment without undergoing any transplantation. Male Wistar rats were divided into three groups. The control group received vehicle (corn oil), and treated groups received CsA 5 or 15 mg/kg, by daily gastric gavage during 8 weeks. The results demonstrated that CsA treatment decreases blood levels of interleukins 1α (IL-1α), 1β (IL-1β) and interleukin 2 (IL-2), but does not alter interleukin 6 (IL-6) and IFN-γ levels. Serum biochemical markers of renal (creatinine) and hepatic (SGPT and SGOT) injury/dysfunction did not vary with CsA treatment, despite the presence of small histological alterations, suggesting that the function of these metabolic organs were preserved. Pulmonary histopathological lesions were observed in the CsA groups, and they were attributed to the activation of the local immunoresponse mechanisms by the normal microbiota in immunosuppressive CsA cases. These results suggest that the CsA concentrations administered in our experimental protocol were able to induce immunosuppression in rats without causing nephro and hepatotoxicity.