New Molecular Bioassays for the Estimation of the Teratogenic Potency of Valproic Acid Derivatives in Vitro: Activation of the Peroxisomal Proliferator-Activated Receptor (PPARδ)

Lampen, Alfonso; Siehler, Sandra; Ellerbeck, Ursula; Göttlicher, Martin; Nau, Heinz

doi:10.1006/taap.1999.8770

Cited by 61 publications

(64 citation statements)

References 51 publications

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“…4B), suggesting a more general mechanism of activation. VPA has also been reported to activate the Rous sarcoma virus promoter and peroxisomal proliferator-activated receptor-␦-dependent transcription in F9 teratocarcinoma cells (6). The effect of VPA on diverse promoters suggests that VPA acts through a mechanism distinct from lithium and may involve direct activation of transcription.…”

Section: Vpa Activates Tcf/lef-dependent Transcription and Synergizesmentioning

confidence: 99%

“…Because HDAC is inhibited by therapeutically relevant concentrations of VPA, and plays important roles in embryonic development (47)(48)(49), it could be the target of VPA-induced teratogenesis. We have therefore investigated whether the structurally related VPA analogues, valpromide (VPM) and 2M2P, which function as anticonvulsants but are not teratogenic in mice (6,7), are able to inhibit HDAC. Under conditions where VPA and trichostatin A (TSA, a well characterized HDAC inhibitor) potently inhibited HDAC, neither VPM nor 2M2P inhibited HDAC in doses ranging from 0.1 to 5 mM (Fig.…”

Section: Vpa Activates Tcf/lef-dependent Transcription and Synergizesmentioning

confidence: 99%

“…Although the target of VPA in this setting is unknown, strict structural requirements have been defined for the teratogenic activity of VPA and VPA-related compounds. Thus, potently teratogenic analogues of VPA contain a tetrahedral ␣-carbon bound to a free carboxyl group, a hydrogen, and two alkyl groups (6,7). In contrast, analogues such as valpromide (VPM), in which the carboxyl group is modified to an amide, and 2-methyl-2-propylpentenoic acid (2M2P), in which a methyl group is added to the ␣-carbon, do not cause neural tube defects in mouse embryos.…”

mentioning

confidence: 99%

“…In contrast, analogues such as valpromide (VPM), in which the carboxyl group is modified to an amide, and 2-methyl-2-propylpentenoic acid (2M2P), in which a methyl group is added to the ␣-carbon, do not cause neural tube defects in mouse embryos. These analogues can still protect against chemically induced seizures in mice (6,7), suggesting that at least some of the clinically observed effects of VPA involve distinct molecular targets.…”

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confidence: 99%

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

Phiel¹,

Zhang²,

Huang³

et al. 2001

Journal of Biological Chemistry

1,570

1,194

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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.

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Section: Vpa Activates Tcf/lef-dependent Transcription and Synergizesmentioning

confidence: 99%

Section: Vpa Activates Tcf/lef-dependent Transcription and Synergizesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Phiel¹,

Zhang²,

Huang³

et al. 2001

Journal of Biological Chemistry

1,570

1,194

View full text Add to dashboard Cite

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“…Some studies suggest that valpromide (similar to VPA, but the carboxyl group is modified to an amide) also has antimanic properties [206]. Valpromide does not inhibit HDAC, does not result in neural tube defects in mouse embryos or the loss of anterior structures that characterizes Xenopus embryos following VPA injection, but does protect against chemically induced seizures in mice [140,[220][221][222][223][224]. Furthermore while the two stereoisomers of VPA have identical antiepileptic properties, only one stereoisomer is teratogenic [224].…”

Section: Valproic Acidmentioning

confidence: 99%

Mood stabilizer psychopharmacology

Gould

Chen

Manji

2002

Clinical Neuroscience Research

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Mood stabilizers represent a class of drugs that are efficacious in the treatment of bipolar disorder. The most established medications in this class are lithium, valproic acid, and carbamazepine. In addition to their therapeutic effects for treatment of acute manic episodes, these medications often are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. While important extracellular effects have not been excluded, most available evidence suggests that the therapeutically relevant targets of this class of medications are in the interior of cells. Herein we give a prospective of a rapidly evolving field, discussing common effects of mood stabilizers as well as effects that are unique to individual medications. Mood stabilizers have been shown to modulate the activity of enzymes, ion channels, arachidonic acid turnover, G protein coupled receptors and intracellular pathways involved in synaptic plasticity and neuroprotection. Understanding the therapeutic targets of mood stabilizers will undoubtedly lead to a better understanding of the pathophysiology of bipolar disorder and to the development of improved therapeutics for the treatment of this disease. Furthermore, the involvement of mood stabilizers in pathways operative in neuroprotection suggests that they may have utility in the treatment of classical neurodegenerative disorders.

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2‐Ethylhexansäure [MAK Value Documentation in German language, 2002]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 35. Lieferung, Ausgabe 2002 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Resorption und Verteilung Metabolismus Elimination Erfahrungen beim Menschen Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung

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New Molecular Bioassays for the Estimation of the Teratogenic Potency of Valproic Acid Derivatives in Vitro: Activation of the Peroxisomal Proliferator-Activated Receptor (PPARδ)

Cited by 61 publications

References 51 publications

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

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

Mood stabilizer psychopharmacology

2‐Ethylhexansäure [MAK Value Documentation in German language, 2002]

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