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.
Highlights
Valproic acid (2-propylvaleric acid, 2-propylpentanoic acid or n-dipropylacetic acid) (see Figure 1(a)), derived from valeric acid (Figure 1(b)) (see Figure 1(c)), was first synthesized in 1882 by Burton [1]
Because valproate is sometimes used in individuals who might be infected with Human herpesvirus 8 (HHV8) and HIV, a recent study aimed to identify the effect of Valproic acid (VPA) in cases of AIDS-associated Kaposi sarcoma [77]
VPA has been used for many years in the treatment of many neurological disorders including convulsive seizures related to epilepsy, as a mood stabilizer and in the treatment of schizophrenia
Summary
Valproic acid (2-propylvaleric acid, 2-propylpentanoic acid or n-dipropylacetic acid) (see Figure 1(a)), derived from valeric acid (Figure 1(b)) (naturally produced by valerian, Valeriana officinalis) (see Figure 1(c)), was first synthesized in 1882 by Burton [1]. Through HDACi activity, VPA enables methylated DNA to be more accessible, which is confirmed by the observation that inhibition of HAT diminishes the demethylation effect triggered by VPA [23, 24]. It has been shown that valproic acid downregulates expression of proteins essential for chromatin maintenance: SMCs 16 (Structural Maintenance of chromatin 1 to 6), DNMT1 (DNA methyl transferase-1), and HP1 (Heterochromatin Protein-1) [25]. Given that the balance of acetylation and deacetylation, under the control of HAT and HDAC, is not restricted to histones [29], it can be hypothesized that VPA, like other HDACi, could modulate molecular activity in addition to transcription. For all the signaling pathways modulated, it has not been established if VPA acts through epigenetic regulation, inhibition of acetylation of molecules other than histones, or by other molecular mechanisms
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