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.

This work was supported by grants from the European Commission (LSHM-CT2004-502987 and FP7-241622), the European Leukodystrophy Association (ELA 2006-043I4), the Spanish Institute for Health Carlos III (FIS PI080991 and FIS PI051118) and the Autonomous Government of Catalonia (2009SGR85) to A.P. S.F. was a fellow of the European Leukodystrophy Association (ELA 2007-018F4). S.K. also received a grant from the European Leukodystrophy Association (ELA 2006-031I4). The work was developed under the COST action BM0604 (to A.P.). The CIBER de Enfermedades Raras is an initiative of the ISCIII. Work carried out at the Department of Experimental Medicine was supported in part by I + D grants from the Spanish Ministry of Science and Innovation (AGL2006-12433 and BFU2009-11879/BFI), the Spanish Ministry of Health (RD06/0013/0012 and PI081843), the Autonomous Government of Catalonia (2009SGR735), ‘La Caixa’ Foundation and COST B35 Action from the European Union. A.N. received a predoctoral fellowship from ‘La Caixa’ Foundation.