Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

Abstract

Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC 50 for HDAC1 ‫؍‬ 0.4 mM). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

“…Valproic acid has been shown to have HDACI activity and to mediate differentiation and/or apoptosis in different carcinoma cell lines in vitro and in vivo (Gottlicher et al, 2001;Phiel et al, 2001;Kramer et al, 2003;Gurvich et al, 2004). Valproic acid also exhibited HDACI activity in cultured thoracic cancer cells.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Subsequently, morphological abnormalities similar to those found in autistic individuals have been reported in animals exposed to valproic acid prenatally (Rodier et al, 1997;Ingram et al, 2000;Miyazaki et al, 2005). Interestingly, valproic acid has been shown to activate Wnt-dependent gene expression by a complex mechanism involving inhibition of GSK3b and histone deacetylase (HDAC) activities (Chen et al, 1999;Phiel et al, 2001;Hall et al, 2002;Bug et al, 2005). Therefore, valproic acid can activate Wnt signaling and thus Wnt signaling may in part explain the teratogenic effect of the drug.…”

Valproic acid inhibits histone deacetylase activity and suppresses excitotoxicity-induced GAPDH nuclear accumulation and apoptotic death in neurons

“…We also examined the effects of valpromide and 2-methyl-2-pentenoic acid, two VPA analogs inactive in blocking HDAC activity. 3 Neither drug in the concentration range of 0.2-1.6 mM was found to be effective in protecting CGC from SYM-induced excitotoxicity following a 6-day pretreatment period starting from 7-DIV (data not shown).…”

“…3,4 HDAC has been catalogued into three classes (for a review, see Gray and Ekstrom 5 ). Class I HDACs consist of HDAC 1, 2, 3, and 8, whereas Class II HDACs include HDAC 4, 5, 6, 7, 9, and 10.…”