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Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy
Stéphane Fourcade1, Montserrat Ruiz, Cristina Guilera
1Neurometabolic Disease Lab, Institut of Neuropathology, Institut d'Investigació Biomèdica de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
Human Molecular Genetics
|February 25, 2010
Summary
Valproic acid (VPA) shows promise for treating X-linked adrenoleukodystrophy (X-ALD). This anti-epileptic drug reduced oxidative damage and VLCFA levels in patients, suggesting a new therapeutic avenue for this fatal neurometabolic disease.
Area of Science:
- Neurology
- Metabolic Disorders
- Genetics
Background:
- X-linked adrenoleukodystrophy (X-ALD) is a fatal, demyelinating neurometabolic disease.
- It stems from the loss of ABCD1, impacting very long-chain fatty acid (VLCFA) metabolism.
- Accumulated hexacosanoic acid causes oxidative protein damage, initiating neurodegeneration.
Purpose of the Study:
- To investigate valproic acid (VPA) as a potential therapeutic for X-ALD.
- To assess VPA's effect on ABCD2 expression and VLCFA metabolism.
- To evaluate VPA's impact on oxidative damage in X-ALD models and patients.
Main Methods:
- Administered VPA to an X-ALD mouse model and conducted a 6-month pilot trial in X-ALD patients.
- Measured ABCD2 expression, VLCFA levels (saturated and monounsaturated), and protein oxidative damage.
- Assessed changes in peripheral blood mononuclear cells.
Main Results:
- VPA induced expression of the ABCD2 transporter, functionally compensating for ABCD1 loss.
- VPA treatment reduced oxidative protein damage and levels of monounsaturated VLCFA (C26:1 n-9).
- ABCD2 overexpression alone prevented oxidative damage in an X-ALD mouse model, and VPA reverted oxidative damage in patients.
Conclusions:
- VPA effectively corrects oxidative damage and impacts VLCFA levels in X-ALD.
- Overexpression of ABCD2 is key to preventing oxidative lesions.
- VPA represents a promising therapeutic strategy for X-ALD, meriting further clinical trials.
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