Structure–function studies for the panacea, valproic acid

Abstract

The anticonvulsant properties of VPA (valproic acid), a branched short-chain fatty acid, were serendipitously discovered in 1963. Since then, therapeutic roles of VPA have increased to include bipolar disorder and migraine prophylaxis, and have more recently been proposed in cancer, Alzheimer's disease and HIV treatment. These numerous therapeutic roles elevate VPA to near 'panacea' level. Surprisingly, the mechanisms of action of VPA in the treatment of many of these disorders remain unclear, although it has been shown to alter a wide variety of signalling pathways and a small number of direct targets. To analyse the mechanism of action of VPA, a number of studies have defined the structural characteristics of VPA-related compounds giving rise to distinct therapeutic and cellular effects, including adverse effects such as teratogenicity and hepatotoxicity. These studies raise the possibility of identifying target-specific novel compounds, providing better therapeutic action or reduced side effects. This short review will describe potential therapeutic pathways targeted by VPA, and highlight studies showing structural constraints necessary for these effects.

An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling

“…VPA is primarily used for the treatment of epilepsy and bipolar disorder treatment, although it has numerous molecular mechanisms and effects (Terbach and Williams, 2009), including the inhibition of cPLA2 (Bazinet et al, 2006) and the regulation of lipid homeostasis (Elphick et al, 2012). Here we show that synapse damage caused by Aβ, is reduced by VPA and a structural derivative (propylisopropylacetic acid (PIA)).…”

Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling

“…The drug is used as antiepileptic and to dampen bipolar disease. The clinical mode of action is supposed to involve inhibition of gamma aminobutyric acid degradation, but it may also involve modulation of ion channels, wnt signaling and altered phosphoi nositol turnover (Rosenberg, 2007;Terbach and Williams, 2009;Williams et al, 2002). Moreover, VPA is a well known develop mental neurotoxicant that induces severe malformations when taken during pregnancy (Ornoy, 2009).…”

Effects of valproic acid on sympathetic activity and left ventricularmyocardial remodelling in rats during pressure overload

“…Regardless of the various opinions on the action of VPA on membrane ion channels, intracellular messenger systems, amino acid release, and metabolism of monoamines, the vast majority of researchers agree that the main neuropharmacological effect of this drug is the enhancement of GABAergic transmission and a rise in GABA levels in the central nervous system (37)(38)(39)(40)(41)(42)(43). In this study, a reduced GABA level in the hypothalamus was observed in the PAAC group, but VPA significantly boosted the GABA level in the region as well as sympathetic inhibition.…”