Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy.
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.
Fourcade
Stéphane
S
Neurometabolic Disease Lab, Institut of Neuropathology, Institut d'Investigació Biomèdica de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
Ruiz
Montserrat
M
Guilera
Cristina
C
Hahnen
Eric
E
Brichta
Lars
L
Naudi
Alba
A
Portero-Otín
Manuel
M
Dacremont
Georges
G
Cartier
Nathalie
N
Wanders
Ronald
R
Kemp
Stephan
S
Mandel
Jean Louis
JL
Wirth
Brunhilde
B
Pamplona
Reinald
R
Aubourg
Patrick
P
Pujol
Aurora
A
D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
C508354:ABCD2 protein, mouse; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D000975:Antioxidants; D015415:Biomarkers; D005227:Fatty Acids; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; D014635:Valproic Acid; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases