Molecular and therapeutic potential and toxicity of valproic acid

Abstract

Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties.

Figure 1

(a) Structure of Valproic acid, (b) structure of valeric acid, (c) valeriana officinalis (valeriana officinalis in an early stage of flowering, [Belgium] Photo by Maarten. © 2007 Erowid.org: http://www.erowid.org/herbs/show_image.php?i=valerian/valeriana_officinalis_flower__i2005e1334_disp.jpg).

Figure 2

Pharmacological activity of VPA described in the literature. Schematic representation of direct and indirect targets of VPA. Principal direct targets known for VPA are ionic channels and ABAT (in green). Epigenetic action of VPA (in violet) as HDACi activity: VPA targets the transcriptomic system and principally directly inhibits HDAC class I (subcategories 1, 2, and 3), and less strongly class II/a (subcategories 4, 5, and 7), but induces HDAC 9 and 11, and indirectly inhibits the function of SMC and DNMT. Probably due to its epigenetic properties, or interactions not yet established, VPA alters, directly or indirectly, expression of many molecules involved in molecular pathways such as apoptosis, inflammation, differentiation, and proliferation (in red).