Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy
Issue date
2010Author
Fourcade, Stéphane
Ruiz, Montserrat
Guilera, Cristina
Hahnen, Eric
Brichta, Lars
Dacremont, Georges
Cartier, Nathalie
Wanders, Ronald
Kemp, Stephan
Mandel, Jean Louis
Wirth, Brunhilde
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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Show full item recordAbstract
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.