title: Mechanisms of Antioxidant Induction with High-Dose N-Acetylcysteine in Childhood Cerebral Adrenoleukodystrophy.
abstract: BACKGROUND
  Childhood cerebral adrenoleukodystrophy (CCALD), a progressive demyelinating disease affecting school-aged boys, causes death within a few years. Oxidative stress is an important contributing factor. N-acetylcysteine (NAC; 280 mg/kg/day) added as adjunctive therapy to reduced-intensity hematopoietic cell transplantation (HCT) improves survival in advanced cases. However, the mechanisms underlying the benefits of NAC are unclear.
  
  
  OBJECTIVE
  The aim of this study was to understand the mechanism of action of NAC in the setting of HCT in CCALD.
  
  
  METHODS
  Immunoassays were carried out to determine changes in heme oxygenase-1 (HO-1) and ferritin expression in plasma samples collected from boys with CCALD at three different timepoints during the course of transplantation. In addition, the induction of HO-1 was also confirmed in normal fibroblasts following incubation with 10-100 µmol/L NAC for 4 h.
  
  
  RESULTS
  Following NAC therapy we observed an increase in expression of the antioxidants HO-1 (~4-fold) and its effector ferritin (~160-fold) in patient samples as compared with baseline. We also observed that NAC exposure significantly increased HO-1 expression in fibroblasts.
  
  
  CONCLUSIONS
  Our data suggest that HO-1 is a possible target protein of NAC and a mediator of its cytoprotective effects in these patients.
authors.affiliation: Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA. rvkartha@umn.edu.|University of Minnesota, Room 4-214, McGuire Translational Research Facility, 2001-6th Street SE, Minneapolis, MN, 55455, USA. rvkartha@umn.edu.
authors.forename: Reena V
authors.initials: RV
authors.lastname: Kartha
authors.affiliation: Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Basso
authors.affiliation: Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Henning
authors.initials: H
authors.lastname: Schröder
authors.affiliation: Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Orchard
authors.affiliation: Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cloyd
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000494:pharmacology; D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000378:metabolism*; D000975:Antioxidants / Q000008:administration & dosage* / Q000494:pharmacology; D001774:Blood Chemical Analysis; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005293:Ferritins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D012333:RNA, Messenger; D005293:Ferritins; D051547:Heme Oxygenase-1; D000111:Acetylcysteine