Mechanisms of Antioxidant Induction with High-Dose N-Acetylcysteine in Childhood Cerebral Adrenoleukodystrophy

CNS Drugs. 2015 Dec;29(12):1041-7. doi: 10.1007/s40263-015-0300-9.


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.

Conclusion: Our data suggest that HO-1 is a possible target protein of NAC and a mediator of its cytoprotective effects in these patients.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / administration & dosage*
  • Acetylcysteine / pharmacology
  • Adolescent
  • Adrenoleukodystrophy / drug therapy*
  • Adrenoleukodystrophy / metabolism*
  • Antioxidants / administration & dosage*
  • Antioxidants / pharmacology
  • Blood Chemical Analysis
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Enzyme-Linked Immunosorbent Assay
  • Ferritins / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Male
  • RNA, Messenger / metabolism
  • Treatment Outcome


  • Antioxidants
  • RNA, Messenger
  • Ferritins
  • Heme Oxygenase-1
  • Acetylcysteine