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      Does Methylene Blue Protect the Kidney Tissues from Damage Induced by Ciclosporin A Treatment?

      research-article
      , , ,
      Nephron
      S. Karger AG
      Thymus, Ciclosporin A, Methylene blue, Kidney, histology

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          Abstract

          Ciclosporin A (CsA) is the first-choice immunosuppressant universally used in allotransplantation and autoimmune diseases. However, it has been demonstrated that this drug produces negative side effects in several organs and in particular in the lymphoid organs and in the kidney. It has been suggested that the CsA causes deleterious effects because it increases the oxygen free radical production. Here we wanted to test whether antioxidants protect the kidney parenchyma from the toxicity induced by CsA. We used methylene blue (MB), because it inhibits the formation of oxygen free radicals. The study was carried out in four groups of Wistar rats. Group I animals were intraperitoneally injected with MB (1 mg/kg/day) for 21 days; group II animals were subcutaneously injected with CsA (15 mg/kg/day) for 21 days; group III animals were treated with CsA combined with MB at the same doses and for the same periods as groups I and II, and group IV animals were injected subcutaneously with olive oil for 21 days as controls. The kidneys and the thymuses were subsequently removed and examined by conventional morphological staining (hematoxylin-eosin and Masson’s trichrome) and enzymatic (NADPH-diaphorase, cytochrome, c oxidase, and superoxide anion production) and immunoenzymatic (inducible nitric oxide synthase – iNOS, endothelial nitric oxide synthase – eNOS) techniques. The thymuses were used to check the persistence of CsA-immunsuppressive effects during MB administration. Group I, III, and IV animals showed a normal kidney architecture and low levels of NADPH-diaphorase and of superoxide anion in all structures studied (proximal and distal tubules, glomeruli and the Henle loops). The cytochrome c oxidase showed a strong activity in proximal tubules, a moderate activity in distal tubules, and a weak activity in glomeruli and in the Henle loops. The expression of iNOS was weak in the proximal tubular epithelial cells and negative in the glomeruli, while eNOS was found to be moderately positive in the glomeruli and in the interstitial arteries, but not in the tubules and in the Henle loops. Degenerative changes with tubulointerstitial injury in the cortex of CsA-treated kidneys (group II) and increases of NADPH-diaphorase levels, iNOS activity, and superoxide staining were found in all structures. The expression of eNOS did not change in group I, III and IV animals. MB combined with CsA prevented the degenerative changes caused by CsA, preserving the structural, enzymatic, and immunoenzymatic integrity of the renal parenchyma. The mechanism by which MB exerts its protective action is not yet clear, but it seems to be due to its ability to inhibit xanthine oxidase and to quench nitric oxide production. Moreover, these data have been also supported by the following: (1) the superoxide anion levels were very high after CsA treatment and reduced after CsA-MB treatment, and (2) the iNOS levels increased in CsA-treated rats and showed normal levels after CsA-MB treatment. Moreover we demonstrated that MB administration did no compromise the CsA immunosuppressive effects, since the thymus showed a cytoarchitecture like that observed in CsA-treated rats.

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          Methylene blue as an inhibitor of superoxide generation by xanthine oxidase

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            Impaired Antioxidant Defense System in the Kidney Tissues from Rabbits Treated with Cyclosporine

            Enzymatic antioxidant defense system and antioxidant defense potential (AOP) were studied in kidney tissue from rabbits treated with cyclosporine (CsA, 25 mg/kg/day), antioxidant vitamins (E, 100 mg/kg/day plus C, 200 mg/kg/day), and CsA plus antioxidant vitamins, and in kidney tissue from control animals. Although no change was observed in superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) and catalase (CAT) activities were found decreased in kidney tissue exposed to CsA for 10 days compared with control tissue. The level of thiobarbituric acid-reagent substances (TBARS) was higher and antioxidant defense potential (AOP) lower in the CsA-treated group compared with the other groups. Histopathological examination reveals important subcellular damage in the renal tissue from the animals treated with CsA. Antioxidant vitamin therapy caused full improvement in the enzyme activities, TBARS levels and AOP, but the subcellular damage was partly ameliorated in the CsA plus vitamin group. Results suggest that CsA impairs the antioxidant defense system and reduces the antioxidant defense potential in the renal tissue. Antioxidant vitamin treatment protects the tissue in part against toxic effects of the drug.
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              Melatonin: an antioxidant protects against cyclosporine-induced nephrotoxicity.

              Cyclosporine (CsA) causes a dose-related decrease in renal function in experimental animals. Different mediators for CsA nephrotoxicity have been suggested; oxygen free radicals are one of them. In experimental model of Wistar rats, the role of antioxidant melatonin (Mel), the main product of pineal secretion, was investigated in CsA nephrotoxicity.
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                Author and article information

                Journal
                NEF
                Nephron
                10.1159/issn.1660-8151
                Nephron
                S. Karger AG
                1660-8151
                2235-3186
                2001
                2001
                10 October 2001
                : 89
                : 3
                : 329-336
                Affiliations
                Division of Human Anatomy, Department of Biomedical Sciences and Biotechnology, University of Brescia, Italy
                Article
                46094 Nephron 2001;89:329–336
                10.1159/000046094
                11598398
                702006f2-272e-420d-9992-178a07debf1d
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 3, Tables: 1, References: 32, Pages: 8
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Thymus,Ciclosporin A,Methylene blue,Kidney, histology
                Cardiovascular Medicine, Nephrology
                Thymus, Ciclosporin A, Methylene blue, Kidney, histology

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