N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy

Tolar, Jakub; Orchard, Paul J.; Bjoraker, Kendra; Ziegler, Richard; Shapiro, Elsa; Charnas, Lawrence

doi:10.1038/sj.bmt.1705571

Cited by 52 publications

(56 citation statements)

References 20 publications

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“…Clinically, NAC is indicated for the treatment of acetaminophen overdose, for the prevention of radiocontrastinduced nephropathy, and as an adjuvant in respiratory conditions with excessive and/or thick mucus production. However, there are contradictory reports on the effects of NAC in clinical (13,14) and animal studies (15-17) of myocardial IR injury. Furthermore, there are limited data specifically focused on NAC use during infancy.…”

Section: Yocardial Ischemia-reperfusion (Ir) Injury Associatedmentioning

confidence: 99%

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

2011

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ABSTRACT:Reactive oxygen species (ROS) are hypothesized to play a key role in myocardial ischemia-reperfusion (IR) injury after cardiopulmonary bypass in children. Clinical studies in adults and several animal models suggest that myocardial IR injury involves cardiomyocyte apoptosis and necrosis. This study investigated a potential relationship between IR-induced ROS production and neonatal cardiomyocyte apoptosis using both in vitro and ex vivo techniques. For in vitro experiments, embryonic rat cardiomyocytes (H9c2 cells) exposed to hypoxia-reoxygenation (HR) showed a timedependent increase in gp91 phox (a marker for ROS production by NADPH oxidases), caspase-3 (a key mediator of apoptosis) expression, and a decrease in the glutathione redox ratio. N-acetylcysteine (NAC; 0.25-2 mM), a potent antioxidant, decreased gp91 phox and caspase-3 expression, inhibited apoptosis and restored the glutathione redox ratio. M yocardial ischemia-reperfusion (IR) injury associatedwith cardiopulmonary bypass and cardioplegic arrest contributes to adverse outcomes after cardiac surgery. The pathogenesis of IR injury is complex, but reactive oxygen species (ROS) generated during IR are thought to play a pivotal role leading to membrane lipid peroxidation, protein denaturation, and DNA modification, all of which may result in irreversible myocyte injury and cell death. Oxygen free radicals are cytotoxic molecules generated during reperfusion and/or reoxygenation of a previously hypoxic tissue bed. The cell damage induced by ROS can also initiate a local inflammatory response, which leads to further oxidant stressmediated tissue damage (1).Several studies have suggested that ROS are involved in the pathogenesis of perinatal asphyxia (2). Neonates, especially those born prematurely, are particularly vulnerable to ROSmediated tissue damage due, in part, to their immature native antioxidant system (3,4). Similarly, myocardial IR injury seems to be a more clinically significant problem in infants after cardiac surgery compared with adults (5-7). Several ROS-producing systems have been identified in many cell types. NADPH oxidase is reported to be a primary source of ROS production in cardiac tissue, and gp91 phox is responsible for the catalytic activity of NADPH oxidase (8,9). Increased ROS induce apoptosis in cardiomyocytes. Caspase-3 protein is a member of the cysteine-aspartic acid protease family that has been identified as being a key mediator of apoptosis in mammalian cells (10,11).N-acetylcysteine (NAC) is a thiol-containing molecule that acts as a free radical scavenger. In addition, NAC is a glutathione precursor that increases intracellular antioxidant capacity (12). Clinically, NAC is indicated for the treatment of acetaminophen overdose, for the prevention of radiocontrastinduced nephropathy, and as an adjuvant in respiratory conditions with excessive and/or thick mucus production. However, there are contradictory reports on the effects of NAC in clinical (13,14) and animal studies (15-17) of myocardial IR injury. Furthe...

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Section: Yocardial Ischemia-reperfusion (Ir) Injury Associatedmentioning

confidence: 99%

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

2011

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“…The central finding is that EDHF-mediated relaxation is compromised in the mice with severe HHcy; interestingly, despite robust increases in arterial SK3 and IK1 expression, the net function of these channels is significantly impaired in the setting of severe HHcy. This pathologic condition corresponds to increased superoxide and nitrotyrosine in the vascular wall, and Cheng et al show also that superoxide scavengers, peroxynitrite inhibitors, or the K ϩ channel opener NS309, which robustly increases channel Ca 2ϩ sensitivity, 6 restore most of the EDHF-mediated relaxation.…”

Section: Channeling the Homocysteine Chapel -------------------------mentioning

confidence: 99%

“…Loss of Krit1, a rap1 effector, leads to cerebral cavernous malformation, which is associated with uncompensated rhoA activation. [4][5][6] Conversely, hemangiomas are associated with elevated rac1/reactive oxygen signaling (see figure 9 ). 7,8 The lessons from the study by Lakshmikanthan et al suggest that rap1 signaling is required for normal vasculature, and that a careful balance of rap1 signaling results in tonic VEGFR2 activation, which allows normal vessels to respond rapidly to an angiogenic stimulus.…”

Section: Beating the Rap In Angiogenesis ----------------------------mentioning

confidence: 99%

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Channeling the homocysteine chapel

Sibinga

2011

Blood

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“…At followup of 7, 8, and 11 months, all patients survived, a significant finding compared to untreated comparators. 40 Besides the provision of antioxidant therapy in the peritransplant period, it stands to reason that RIC regimens may spare toxicity to the vulnerable cALD CNS and promote more favorable functional survival following HCT. To this end, Awaya et al reported outcomes after an RIC regimen followed by HLA-matched UCBT for a boy with advanced …”

Section: Transplant Limitations and Unknownsmentioning

confidence: 99%

Stem cell-transplantation therapy for adrenoleukodystrophy: current perspectives

Miller¹

2017

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Adrenoleukodystrophy (ALD) is a rare, X-linked peroxisomal disorder of impaired very long-chain fatty-acid metabolism. It results from various mutations in the ABCD1 gene (Xq28). All males with the biochemical defect of ALD are at risk of developing cerebral whitematter disease (cALD) during their lifetime. Thirty-five percent of ALD patients develop cALD in boyhood, a life-threatening phenotype characterized by rapidly expanding, neuroinflammatory demyelination and irreversible clinical neurologic decline. The ABCD1 genotype does not predict susceptibility to or protection from the childhood cALD phenotype; therefore, clinicians must remain ever vigilant for its development when monitoring ALD patients. Currently, allogeneic hematopoietic cell transplantation (HCT) is the standard of care for boyhood cALD. While HCT provides dramatic functional survival benefit in boys with early, presymptomatic cALD, outcomes are less favorable and less predictable for those with more advanced disease. Furthermore, little is known about how successful HCT in childhood might impact the onset of central nervous system disease in adulthood. Finally, investigations of experimental gene-therapy strategies are ongoing. This review explores current perspectives of stem cell transplantation in cALD.

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N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy

Cited by 52 publications

References 20 publications

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

Impact of N-Acetylcysteine on Neonatal Cardiomyocyte Ischemia-Reperfusion Injury

Channeling the homocysteine chapel

Stem cell-transplantation therapy for adrenoleukodystrophy: current perspectives

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