Reena V Kartha1,2, Jie Zhou3, Lisa Basso4, Henning Schröder5, Paul J Orchard4, James Cloyd3. 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.
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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