title: Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver.
abstract: Cyclosporine A (CsA) is the most widely used immunosuppressive drug for preventing graft rejection and autoimmune disease. However, the therapeutic treatment induces several side effects such as nephrotoxicity, cardiotoxicity, hypertension and hepatotoxicity. Among possible mechanisms of CsA-induced hepatic damage, oxidative stress has been suggested. Melatonin (Mel) has been successfully used as a potent antioxidant against many pathophysiological states. This experimental study was performed to test, during CsA treatment, the alterations of some heat shock proteins (HSP) and the Mel antioxidant properties against CsA-induced injury. Rats were divided into four groups, which were treated respectively with olive oil, Mel alone, CsA and CsA plus Mel for 30 days. At the end of the treatments, the animals were killed and hepatic tissue was treated for morphological (haematoxylin-eosin), biochemical (reduced glutathione, GSH and malondialdehyde, MDA) and immunohistochemical (HSP60, HSP72, GRP75 and MT) analyses. The results indicate that CsA-induced hepatotoxicity was characterised by morphological alterations in tissue architecture, changes in GSH and MDA levels and increase in stress protein expression. In conclusion, our data suggest that the imbalance between production of free oxygen radicals and antioxidant defence systems, due to CsA administration, is a mechanism responsible for oxidative stress. Moreover, we show that Mel plays a protective action against CsA-induced oxidative stress, as supported by biochemical and immunohistochemical results.
authors.affiliation: Department of Biomedical Sciences and Biotechnology, Division of Human Anatomy, University of Brescia, 25123 Brescia, Italy. rezzani@med.unibs.it
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.forename: Barbara
authors.initials: B
authors.lastname: Buffoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Rodella
authors.forename: Alessandra
authors.initials: A
authors.lastname: Stacchiotti
authors.forename: Rossella
authors.initials: R
authors.lastname: Bianchi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D018834:Chaperonin 60 / Q000302:isolation & purification; D056486:Chemical and Drug Induced Liver Injury; D016572:Cyclosporine / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D018840:HSP70 Heat-Shock Proteins / Q000302:isolation & purification; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000302:isolation & purification; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008099:Liver / Q000737:chemistry / Q000187:drug effects; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D008550:Melatonin / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000302:isolation & purification; D008668:Metallothionein / Q000032:analysis; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D018834:Chaperonin 60; D018840:HSP70 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C018551:glucose-regulated proteins; D008315:Malondialdehyde; D016572:Cyclosporine; D008668:Metallothionein; D005978:Glutathione; D008550:Melatonin