Valproic acid

Ej, Lammer; Le, Sever; Gp, Oakley

doi:10.1002/tera.1420350319

Cited by 256 publications

(35 citation statements)

References 36 publications

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“…Estimations of prevalence of NTD due to exposure to the anticonvulsant valproic acid range from 1 to 2% and with carbamazepine exposure at about 0.5% [12, 13]. These rates are about 10 times higher than the population rate.…”

Section: What Causes Ntds?mentioning

confidence: 94%

Genetic Studies in Neural Tube Defects

et al. 2000

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Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families.

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Section: What Causes Ntds?mentioning

confidence: 94%

Genetic Studies in Neural Tube Defects

et al. 2000

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“…Valproic acid (VPA) (2-propyl pentanoic acid), widely used in treating epilepsy and bipolar disorder, 8,9) has recently received attention as an anti-tumor agent, 10) but it causes hepatic damage, pancreatitis, hyperammonemia, and depression of the central nervous system, 11) and exposure to it in early pregnancy is a risk factor for spina bifida 12,13) and autism. 14,15) Although histone deacetylase 16) and glycogen synthase kinase 3 17,18) have been reported to be intracellular targets of VPA, the mechanisms responsible for the side effects of VPA are not well understood.…”

mentioning

confidence: 99%

Apoptotic Cell Death in the Fission YeastSchizosaccharomyces pombeInduced by Valproic Acid and Its Extreme Susceptibility to pH Change

Mutoh

Kitajima

Ichihara

2011

Bioscience, Biotechnology, and Biochemistry

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Schizosaccharomyces pombe treated with valproic acid died with apoptotic markers such as DNA fragmentation, loss of a mitochondrial electrochemial gradient and chromatin condensation, independently of metacaspase, a yeast homolog of metazoan caspase. Sensitivity to valproic acid was strongly dependent on growth phase. Cells in a later growth phase were much more sensitive to valproic acid than those in an earlier one. Altering the pH of the medium with HCl and with NaOH also caused remarkable changes in sensitivity. Cells in an acidic medium were more sensitive to valproic acid. This pH-dependent change in sensitivity did not require de novo protein synthesis, and a change in pH 60 min after the administration of valproic acid affected sensitivity. These results suggest that the intracellular cell death process was susceptible to extracellular pH. Although a sir2 mutant of Saccharomyces cerevisiae has been reported to be resistant to valproic acid, mutations in sir2 did not affect the sensitivity to valproic acid of S. pombe.

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“…In this study we used spotted cDNA microarrays to monitor global gene expression changes in response to the antiepileptic drug valproic acid (VPA), a potent teratogen that most notably induces neural tube defects (NTDs) in human, mouse, and other vertebrate embryos (Lammer et al 1987; Nau et al 1991; Oberemm and Kirschbaum 1992; Whitsel et al 2002). NTDs with varying penetrance can be induced in the mouse embryo by many chemical treatments (Copp et al 1990) and by the functional disruption of a plethora of genes (Copp et al 2003; Juriloff and Harris 2000).…”

mentioning

confidence: 99%

Valproic Acid Teratogenicity: A Toxicogenomics Approach

Kultima¹,

Nyström²,

Scholz³

et al. 2004

Environ Health Perspect

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Embryonic development is a highly coordinated set of processes that depend on hierarchies of signaling and gene regulatory networks, and the disruption of such networks may underlie many cases of chemically induced birth defects. The antiepileptic drug valproic acid (VPA) is a potent inducer of neural tube defects (NTDs) in human and mouse embryos. As with many other developmental toxicants however, the mechanism of VPA teratogenicity is unknown. Using microarray analysis, we compared the global gene expression responses to VPA in mouse embryos during the critical stages of teratogen action in vivo with those in cultured P19 embryocarcinoma cells in vitro. Among the identified VPA-responsive genes, some have been associated previously with NTDs or VPA effects [vinculin, metallothioneins 1 and 2 (Mt1, Mt2), keratin 1-18 (Krt1-18)], whereas others provide novel putative VPA targets, some of which are associated with processes relevant to neural tube formation and closure [transgelin 2 (Tagln2), thyroid hormone receptor interacting protein 6, galectin-1 (Lgals1), inhibitor of DNA binding 1 (Idb1), fatty acid synthase (Fasn), annexins A5 and A11 (Anxa5, Anxa11)], or with VPA effects or known molecular actions of VPA (Lgals1, Mt1, Mt2, Id1, Fasn, Anxa5, Anxa11, Krt1-18). A subset of genes with a transcriptional response to VPA that is similar in embryos and the cell model can be evaluated as potential biomarkers for VPA-induced teratogenicity that could be exploited directly in P19 cell–based in vitro assays. As several of the identified genes may be activated or repressed through a pathway of histone deacetylase (HDAC) inhibition and specificity protein 1 activation, our data support a role of HDAC as an important molecular target of VPA action in vivo.

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Valproic acid

Cited by 256 publications

References 36 publications

Genetic Studies in Neural Tube Defects

Genetic Studies in Neural Tube Defects

Apoptotic Cell Death in the Fission YeastSchizosaccharomyces pombeInduced by Valproic Acid and Its Extreme Susceptibility to pH Change

Valproic Acid Teratogenicity: A Toxicogenomics Approach

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