Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy.

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.

• Authors: Stéphane Fourcade, Montserrat Ruiz, Cristina Guilera, Eric Hahnen, Lars Brichta, Alba Naudi, Manuel Portero-Otín, Georges Dacremont, Nathalie Cartier, Ronald Wanders, Stephan Kemp, Jean Louis Mandel, Brunhilde Wirth, Reinald Pamplona, Patrick Aubourg, Aurora Pujol
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 10 Pg. 2005-14 (May 15 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 20179078 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCD2 protein, mouse
• ATP Binding Cassette Transporter, Subfamily D
• ATP-Binding Cassette Transporters
• Antioxidants
• Biomarkers
• Fatty Acids
• Histone Deacetylase Inhibitors
• Reactive Oxygen Species
• Valproic Acid
• Acetyltransferases
• Fatty Acid Elongases

Topics

• ATP Binding Cassette Transporter, Subfamily D
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Acetyltransferases (genetics, metabolism)
• Adolescent
• Adrenoleukodystrophy (drug therapy, enzymology, pathology)
• Animals
• Antioxidants (pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Child
• Fatty Acid Elongases
• Fatty Acids (metabolism)
• Fibroblasts (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Leukocytes, Mononuclear (drug effects, metabolism)
• Mice
• Oxidative Stress (drug effects)
• Rats
• Rats, Wistar
• Reactive Oxygen Species (metabolism)
• Spinal Cord (drug effects, pathology)
• Valproic Acid (pharmacology, therapeutic use)