title: The long-term administration of calcineurin inhibitors decreases antioxidant enzyme activity in the rat parotid and submandibular salivary glands.
abstract: OBJECTIVE
  Calcineurin inhibitors are widely used for prevention of graft rejection and treatment of autoimmune disorders, which result in increased longevity and enhanced quality of life for patients. Unfortunately, the toxic side effects of these drugs (mainly renal, hepatic and cardiac) limit their use. In this work, we studied the effects of long-term treatment of rats with the immunosuppressant cyclosporin (CsA) or tacrolimus (Tac) on salivation, saliva composition and on the major salivary glands (parotid and submandibular) in terms of histological alterations and oxidative stress, evaluated as lipoperoxidation (thiobarbituric acid reactive species--TBARS) and antioxidant enzyme activity contents (superoxide dismutase--SOD, catalase--CAT and glutathione peroxidase--GPx).
  
  
  METHODS
  Male adult rats were treated with either CsA (10 mg/kg/day) or Tac (1 mg/kg/day) subcutaneously for 30 or 60 days. At the end of the experimental periods, pilocarpine-stimulated salivary flow rate was measured, saliva samples were collected and the salivary glands were dissected for morphological and biochemical analyses.
  
  
  RESULTS
  After a 60-day treatment with any of the immunosuppressants, the total protein, Ca(2+) and Na(+) saliva concentrations were decreased but salivary flow rates were unaffected. In addition, both parotid and submandibular glands showed decreased SOD, CAT and GPx activities, increased TBARS contents and histomorphological alterations involving the epithelium and acini.
  
  
  CONCLUSIONS
  Based on these results, we suggest that the systemic long-term administration of the calcineurin inhibitor CsA or Tac induces an impairment of the antioxidant enzymatic defense in the rat major salivary glands, which may, in turn, lead to altered saliva composition.
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil. Electronic address: lcs@foar.unesp.br.
authors.forename: Luís C
authors.initials: LC
authors.lastname: Spolidorio
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Bruno S
authors.initials: BS
authors.lastname: Herrera
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil.
authors.forename: Leila S
authors.initials: LS
authors.lastname: Coimbra
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil.
authors.forename: Cleverton R
authors.initials: CR
authors.lastname: de Andrade
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil.
authors.forename: Denise M P
authors.initials: DM
authors.lastname: Spolidorio
authors.affiliation: Department of Physiology and Pathology, Dental School of Araraquara, State University of São Paulo (UNESP), Araraquara, SP, Brazil.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rossa Junior
authors.affiliation: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil.
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscará
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism*; D010306:Parotid Gland / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012463:Saliva / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D013363:Submandibular Gland / Q000378:metabolism* / Q000473:pathology; D016559:Tacrolimus / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D010088:Oxidoreductases; D016559:Tacrolimus
keywords: Cyclosporin; Oxidative stress; Salivary glands; Tacrolimus