Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy

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2010
Author
Fourcade, Stéphane
Ruiz, Montserrat
Guilera, Cristina
Hahnen, Eric
Brichta, Lars
Naudí i Farré, Alba
Portero Otín, Manuel
Dacremont, Georges
Cartier, Nathalie
Wanders, Ronald
Kemp, Stephan
Mandel, Jean Louis
Wirth, Brunhilde
Pamplona Gras, Reinald
Aubourg, Patrick
Pujol, Aurora
Suggested citation
Fourcade, Stéphane; Ruiz, Montserrat; Guilera, Cristina; Hahnen, Eric; Brichta, Lars; Naudí i Farré, Alba; ... Pujol, Aurora. (2010) . Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Human Molecular Genetics, 2010, vol. 19, núm. 10, p. 2005-2014. https://doi.org/10.1093/hmg/ddq082.
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Abstract
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.
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http://hdl.handle.net/10459.1/58675
DOI
https://doi.org/10.1093/hmg/ddq082
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Human Molecular Genetics, 2010, vol. 19, núm. 10, p. 2005-2014
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