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

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

Author information

1
Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA. rvkartha@umn.edu.
2
University of Minnesota, Room 4-214, McGuire Translational Research Facility, 2001-6th Street SE, Minneapolis, MN, 55455, USA. rvkartha@umn.edu.
3
Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA.
4
Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
5
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.

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.

CONCLUSION:

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

PMID:
26670322
DOI:
10.1007/s40263-015-0300-9
[Indexed for MEDLINE]

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