Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy
Mandel, Jean Louis
MetadataShow full item record
X-linked adrenoleukodystrophy (X-ALD) is a fatal, axonal demyelinating, neurometabolic disease. It results from the functional loss of a member of the peroxisomal ATP-binding cassette transporter subfamily D (ABCD1), which is involved in the metabolism of very long-chain fatty acids (VLCFA). Oxidative damage of proteins caused by excess of the hexacosanoic acid, the most prevalent VLCFA accumulating in X-ALD, is an early event in the neurodegenerative cascade. We demonstrate here that valproic acid (VPA), a widely used anti-epileptic drug with histone deacetylase inhibitor properties, induced the expression of the functionally overlapping ABCD2 peroxisomal transporter. VPA corrected the oxidative damage and decreased the levels of monounsaturated VLCFA (C26:1 n-9), but not saturated VLCFA. Overexpression of ABCD2 alone prevented oxidative lesions to proteins in a mouse model of X-ALD. A 6-month pilot trial of VPA in X-ALD patients resulted in reversion of the oxidative damage of proteins in peripheral blood mononuclear cells. Thus, we propose VPA as a promising novel therapeutic approach that warrants further clinical investigation in X-ALD.
Is part ofHuman Molecular Genetics, 2010, vol. 19, núm. 10, p. 2005-2014
European research projects
Showing items related by title, author, creator and subject.
Ranea-Robles, Pablo; Launay, Nathalie; Ruiz, Montserrat; Calingasan, Noel Ylagan; Dumont, Magali; Naudí i Farré, Alba; Portero Otín, Manuel; Pamplona Gras, Reinald; Ferrer, Isidre; Beal, M. Flint; Fourcade, Stéphane; Pujol, Aurora (Wiley Open Access, 2018)The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and ...
Oxidative damage compromises energy metabolism in the axonal degeneration mouse model of X-Adrenoleukodystrophy Fourcade, Stéphane; Schlüter, Agatha; López Erauskin, Jone; Guilera, Cristina; Jové Font, Mariona; Naudí i Farré, Alba; García Arumí, Elena; Andreu, Antoni L.; Starkov, Anatoly A.; Pamplona Gras, Reinald; Ferrer, Isidre; Portero Otín, Manuel; Pujol, Aurora (Mary Ann Liebert, Inc., 2011)Aims: Chronic metabolic impairment and oxidative stress are associated with the pathogenesis of axonal dysfunction in a growing number of neurodegenerative conditions. To investigate the intertwining of both noxious factors, ...
Morató, Laia; Ruiz, M.; Boada Pallàs, Jordi; Calingasan, Noel Ylagan; Galino, Jorge; Guilera, Cristina; Jové Font, Mariona; Naudí i Farré, Alba; Ferrer, Isidre; Pamplona Gras, Reinald; Serrano, M.; Portero Otín, Manuel; Beal, M. F.; Fourcade, Stéphane; Pujol, Aurora (Macmillan Publishers, 2015)Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the ...