J Pharm Pharmacogn Res 2(Suppl. 1): S12, 2014
Special supplement with the abstract book of LATINFARMA 2013
CO 023: TRIMETAZIDINE INHIBITS THE RENAL FIBROSIS INDUCED BY CYCLOSPORIN A
De la Cruz Rodríguez L, Rey M, Honoré S, Oldano A, Araujo C.Facultad de Bioquímica Química y Farmacia. Universidad Nacional de Tucumán, Balcarce 747. (4000) San Miguel de Tucumán, Argentina. E-mail: email@example.com
Introduction: Cyclosporin A (CyA) is an immunosuppressor used in transplanted patients. Adverse effects like as nephrotoxicity and hepatotoxicity, have been described. Our previous papers demonstrated that Trimetazidine (TMZ) is able to reverse the CyAinduced nephrotoxicity.
Objectives: contribute to the knowledge of the mechanisms of action of TMZ in renal fibrosis induced by CyA.
Material and methods: The experimental design was carried out for 120 days. Included four groups (n = 8) of male Wistar rats treated with: A control. B treated with CyA (25 mg/kg/day). C treated with TMZ (20 mg/kg/day). D treated TMZ for 20 days (20 mg/kg/day), them for 120 days with TMZ (20 mg/kg/day) and CyA (25 mg/kg/day). Urea and serum creatinine as well as the excretion of urinary gamma glutamyl transpeptidase were determined. Structural studies were performed with hematoxylin-eosin and Mallory staining to evidence the renal fibrosis. Fibrosis was quantified using the Image Pro Plus software (NIH). By Transmission electron microscope (TEM) the renal ultrastructure was analyzed. Transforming Growth Factor beta and Collagen I were evidenced by immunohistochemistry.
Results: animals treated with 25 mg CyA/kg/day presented hydropic degeneration with nuclei displaced and in some cases are found in the tubular lumen, observed by optical microscopy. Ultrastructure analyzed by TEM showed edematous mitochondria with loss of its internal structure. Interstitial fibrosis was confirmed by evidenced immunohistochemistry Transforming Growth Factor Beta and Collagen I using specific antibodies. Pre-treatment with TMZ for 20 days and the synergistic treatment TMZ+CyA, showed biochemical parameters within the reference values and preserved cytoarchitecture, with negative immunohistochemistry to the markers studied.
Conclusions: Interstitial fibrosis induced by CyA was dose and time dependent. The production of inflammatory mediators, Transforming Growth Factor Beta and the synthesis of Collagen I, would be inhibited by TMZ.