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

Reena V Kartha, Jie Zhou, Lisa Basso, Henning Schröder, Paul J Orchard, James Cloyd

Journal: CNS drugs 2016;29(12):1041-7

PMID: 26670322

Full Text on Ovid Technologies, Inc. View on PubMed

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.

Address: Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA. [email protected].; University of Minnesota, Room 4-214, McGuire Translational Research Facility, 2001-6th Street SE, Minneapolis, MN, 55455, USA. [email protected].; Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA.; Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.; Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA.

DOI: 10.1007/s40263-015-0300-9

Link outs

Free resources

Medical:

https://medlineplus.gov/antioxidants.html

Subscription / membership required

Full Text Sources:

MeSH Terms: Acetylcysteine, Adolescent, Adrenoleukodystrophy, Antioxidants, Blood Chemical Analysis, Cells, Cultured, Child, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Ferritins, Fibroblasts, Heme Oxygenase-1, Humans, Male, RNA, Messenger, Treatment Outcome