1.
Biomarker Identification, Safety, and Efficacy of High-Dose Antioxidants for Adrenomyeloneuropathy: a Phase II Pilot Study.
Casasnovas, C, Ruiz, M, Schlüter, A, Naudí, A, Fourcade, S, Veciana, M, Castañer, S, Albertí, A, Bargalló, N, Johnson, M, et al
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2019;(4):1167-1182
-
-
Free full text
-
Abstract
X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260.
2.
Double-edged sword behaviour of gallic acid and its interaction with peroxidases in human microvascular endothelial cell culture (HMEC-1). Antioxidant and pro-oxidant effects.
Serrano, J, Cipak, A, Boada, J, Gonzalo, H, Cacabelos, D, Cassanye, A, Pamplona, R, Zarkovic, N, Portero-Otin, M
Acta biochimica Polonica. 2010;(2):193-8
Abstract
A previous report from our group had shown in vitro a direct interaction between peroxidases and dietary antioxidants at physiological concentrations, where in the absence of H(2)O(2), the antioxidants could serve as oxidizing substrates for the peroxidases. However, the physiological relevance of those findings had not been evaluated. The main objective of this study was to determine whether the oxidizing products produced in the interaction between peroxidase and gallic acid at a physiological concentration of 1 microM may promote cell death or survival in a human microvascular endothelial cell line (HMEC-1). Our findings suggested that gallic acid may show a double-edged sword behaviour, since in the absence of H(2)O(2) it may have a pro-oxidant effect which may promote cell injury (evidenced by LDH, Crystal Violet and calcein AM viability/citotoxicity assays), while in the presence of H(2)O(2), gallic acid may act as an antioxidant inhibiting oxidative species produced in the peroxidase cycle of peroxidases. These observations were confirmed with several oxidative stress biomarkers and the evaluation of the activation of cell survival pathways like AKT and MAPK/ERK.