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

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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.

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Author contributions

Designed the experiments: RVK, JZ, LB, HS, PJO, JC. Performed the experiments: JZ, RVK, LB. Analyzed the data: JZ, RVK, LB, HS. Contributed essential reagents/tools: PJO, JC, HS. Wrote the paper: RVK, JZ, LB, HS, PJO, JC.

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Author notes

    Authors and Affiliations

    1. Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, University of Minnesota, Minneapolis, MN, USA

      Reena V. Kartha, Jie Zhou & James Cloyd

    2. Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA

      Henning Schröder

    3. Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA

      Lisa Basso & Paul J. Orchard

    4. University of Minnesota, Room 4-214, McGuire Translational Research Facility, 2001-6th Street SE, Minneapolis, MN, 55455, USA

      Reena V. Kartha

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    1. Reena V. Kartha
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    2. Jie Zhou
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    Corresponding author

    Correspondence to Reena V. Kartha.

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    Funding

    The study was funded by a University of Minnesota Academic Health Center Faculty Development Grant to JC and PJO.

    Conflict of interest

    RVK, JZ, LB, HS, PJO, and JC declare that they have no conflicts of interest.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

    Additional information

    R. V. Kartha and J. Zhou contributed equally to this work.

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    Kartha, R.V., Zhou, J., Basso, L. et al. Mechanisms of Antioxidant Induction with High-Dose N-Acetylcysteine in Childhood Cerebral Adrenoleukodystrophy. CNS Drugs 29, 1041–1047 (2015). https://doi.org/10.1007/s40263-015-0300-9

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