Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity

Semmler, Alexander; Frisch, Christian; Bleul, Christiane; Smith, Desirée E.C.; Bigler, Laurent; Prost, Jean-Christophe; Blom, Henk J.; Linnebank, Michael

doi:10.1016/j.seizure.2017.01.003

Cited by 19 publications

(19 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prenatal VPA exposure of neuronal cultures from the cerebral cortices of prenatal mice embryos was shown to decrease the total number, total length, and complexity of neuronal dendrites [36]. Similarly, results obtained by Semmler et al [37] indicated that intrauterine VPA exposure caused dose-dependent neuronal cell number alterations in the hippocampal areas CA1/2 and the CA3 region and in folic acid metabolism in a rat model of valproate teratogenicity. On the other hand, VPA appears to cooperate in neuroprotection and cognitive enhancement by inhibition of histone deacetylase (HDAC) activity [38].…”

Section: Discussionmentioning

confidence: 85%

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

Andres-Mach

Zagaja

Haratym-Maj

et al. 2017

IJMS

View full text Add to dashboard Cite

Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy.

show abstract

Section: Discussionmentioning

confidence: 85%

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

Andres-Mach

Zagaja

Haratym-Maj

et al. 2017

IJMS

View full text Add to dashboard Cite

show abstract

“…Numerous mechanisms have been proposed by which VPA may disrupt NT closure. These include epigenetic dysregulation ( Tung and Winn, 2010 ), inhibition of folate metabolism ( Fathe et al, 2014 , Roy et al, 2008 , Semmler et al, 2017 ), suppression of nitric oxide signalling ( Tiboni et al, 2013 , Tiboni and Ponzano, 2015 ) and increased reactive oxygen species production ( Akimova et al, 2017 , Tung and Winn, 2011 ). In addition, VPA's anti-acetylation effects may disrupt post-translational modifications of other effector proteins including those involved in actin regulation.…”

Section: Discussionmentioning

confidence: 99%

Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos

Hughes¹,

Greene²,

Copp³

et al. 2018

Mechanisms of Development

View full text Add to dashboard Cite

Failure of neural tube closure in the early embryo causes neural tube defects including spina bifida. Spina bifida lesions predominate in the distal spine, particularly after exposure to the anticonvulsant valproic acid (VPA). How VPA specifically disturbs late stages of neural tube closure is unclear, as neurulation is usually viewed as a uniform ‘zippering’ process along the spine. We recently identified a novel closure site (“Closure 5”) which forms at the caudal extremity of the mouse posterior neuropore (PNP) when completion of closure is imminent. Here we investigated whether distal spina bifida in VPA-exposed embryos involves disruption of Closure 5. Exposure of E8.5 mouse embryos to VPA in whole embryo culture had marked embryotoxic effects, whereas toxic effects were less pronounced in more developmentally advanced (E9) embryos. Only 33% of embryos exposed to VPA from E9 to E10.5 achieved PNP closure (control = 90%). Short-term (8 h) VPA treatment diminished supra-cellular F-actin cables which normally run along the lateral neural folds, and prevented caudal PNP narrowing normally characteristic of Closure 5 formation. Laser ablation of Closure 5 caused rapid neuropore widening. Equivalent ablations of the caudal PNP in VPA treated embryos resulted in significantly less widening, suggesting VPA prevents formation of Closure 5 as a biomechanically active structure. Thus, VPA exposure prevents morphological and biomechanical conversion of the caudal extreme of the PNP during late spinal closure. Closure 5 facilitates neural fold apposition when completion of closure is imminent, such that its disruption in VPA-exposed embryos may lead to distal spina bifida.

show abstract

“…Regarding the molecular mechanism of action of this drug, a recent study performed in a rat model of teratogenesis showed that intrauterine VPA exposure caused a decrease in the number of astrocytes in the developing hippocampus. This study also explored the mechanistic role of this molecule and found that VPA produced an increase in the concentration of 5‐methyl‐tetrahydrofolate (THF) in the brain of newborn pups, suggesting a role of VPA on folate metabolism (Semmler et al, ). Moreover, another study showed conclusively that VPA interfered with the EMT of NCCs in culture, thereby suggesting the role of VPA as a potent NC teratogen (Fuller, Cornelius, Murphy, & Wiens, ).…”

Section: Chemical Agentsmentioning

confidence: 99%

The role of teratogens in neural crest development

Cerrizuela

Vega-Lopez

Aybar

2020

Birth Defects Research

View full text Add to dashboard Cite

The neural crest (NC), discovered by Wilhelm His 150 years ago, gives rise to a multipotent migratory embryonic cell population that generates a remarkably diverse and important array of cell types during the development of the vertebrate embryo. These cells originate in the neural plate border (NPB), which is the ectoderm between the neural plate and the epidermis. They give rise to the neurons and glia of the peripheral nervous system, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies are a class of congenital diseases resulting from the abnormal induction, specification, migration, differentiation or death of NC cells (NCCs) during embryonic development and have an important medical and societal impact. In general, congenital defects affect an appreciable percentage of newborns worldwide. Some of these defects are caused by teratogens, which are agents that negatively impact the formation of tissues and organs during development. In this review, we will discuss the teratogens linked to the development of many birth defects, with a strong focus on those that specifically affect the development of the NC, thereby producing neurocristopathies.Although increasing attention is being paid to the effect of teratogens on embryonic development in general, there is a strong need to critically evaluate the specific role of these agents in NC development. Therefore, increased understanding of the role of these factors in NC development will contribute to the planning of strategies aimed at the prevention and treatment of human neurocristopathies, whose etiology was previously not considered.

show abstract

Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity

Abstract: This study shows that intrauterine VPA exposure is associated with changes in hippocampal cell numbers in the CA1/2 and CA3 region and in folate metabolism.

Cited by 19 publications

References 45 publications

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

Valproic acid disrupts the biomechanics of late spinal neural tube closure in mouse embryos

The role of teratogens in neural crest development

Contact Info

Product

Resources

About