Valproic acid decreases cell proliferation and migration in the cerebellum of zebrafish larvae

Lee, Yunkyoung; Lee, Bongkyu; Lee, Chang‐Joong

doi:10.1080/19768354.2014.905491

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…We demonstrated that VPA exposure reduced the number of neuronal progenitor cells in Tg( nestin:GFP ) embryos. This result is congruent with previous findings showing that VPA exposure decreases the proliferation of neuronal progenitor cells in the telencephalon 42 and cerebellum 37 of larval zebrafish brain. It remains largely unclear how VPA affects the proliferation of neuronal progenitor cells in the brain; the decrease in progenitor cells may result from drug‐induced apoptosis 37 or inhibition of cell proliferation 42 .…”

Section: Discussionsupporting

confidence: 93%

“…36 Next, we demonstrated that VPA exposure increased the hindbrain midline gap in developing zebrafish embryos. This malformation might be caused by a reduction in neuronal cell migration, 37 or might be described as a cranial NTD that is analogous to human fetal VPA-related cranial NTDs. 38 Further studies will be required to make a distinction between these mechanisms.…”

Section: F I G U R Ementioning

confidence: 99%

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Folic acid supplementation rescues valproic acid‐induced developmental neurotoxicity and behavioral alterations in zebrafish embryos

et al. 2021

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Objective: Fetal exposure to the anticonvulsant drug valproic acid (VPA), used to treat certain types of epilepsy, increases the risk for birth defects, including neural tube defects, as well as learning difficulties and behavioral problems. Here, we investigated neurotoxic effects of VPA exposure using zebrafish as a model organism. The capacity of folic acid (FA) supplementation to rescue the VPA-induced neuronal and behavioral perturbations was also examined. Methods: Zebrafish embryos of different transgenic lines with neuronal green fluorescent protein expression were exposed to increasing concentrations of VPA with or without FA supplementation. Fluorescence microscopy was used to visualize alterations in brain structures and neural progenitor cells, as well as motor neurons and neurite sprouting. A twitching behavioral assay was used to examine the functional consequences of VPA and FA treatment. Results: In zebrafish embryos, VPA exposure caused a decrease in the midbrain size, an increase in the midline gap of the hindbrain, and perturbed neurite sprouting of secondary motor neurons, in a concentration-dependent manner. VPA exposure also decreased the fluorescence intensity of neuronal progenitor cells in early developmental stages, indicating fewer cells. Furthermore, VPA exposure significantly altered embryonic twitching activity, causing hyperactivity in dark and hypoactivity in light. Supplementation of FA rescued the VPA-induced smaller midbrain size and hindbrain midline gap defects. FA treatment also increased the number of neuronal progenitor cells in VPA-treated embryos and salvaged neurite sprouting of the secondary motor neurons. FA rescued the VPA-induced alterations in twitching activity in light but not in dark. Significance: We conclude that VPA exposure induces specific neurotoxic perturbations in developing zebrafish embryos, and that FA reversed most of the identified defects. The results demonstrate that zebrafish is a promising model to study VPAinduced teratogenesis and to screen for countermeasures. |MUHSEN Et al.

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Section: Discussionsupporting

confidence: 93%

Section: F I G U R Ementioning

confidence: 99%

Folic acid supplementation rescues valproic acid‐induced developmental neurotoxicity and behavioral alterations in zebrafish embryos

et al. 2021

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“…This coincides with the period of VPA exposure in this study, suggesting that the drug has significant effects on cellular organization during cerebellar histogenesis. The observed behavioral and morphological phenotypes align with characteristics associated with ASD, such as reduced brain size and dysregulation of neuronal proliferation and migration [62][63][64][65][66].…”

Section: Discussionsupporting

confidence: 60%

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

Flores-Prieto,

Caycho-Salazar,

Manzo

et al. 2024

Preprint

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The etiology of Autism Spectrum Disorder (ASD) has been linked to both genetic and epigenetic factors. Among the epigenetic factors, exposure to valproic acid (VPA), an antiepileptic and mood-modulating drug, has been shown to induce characteristic traits of ASD when exposed during embryogenesis. Conversely, in animal models, Enriched Environment (EE) has demonstrated positive behavioral and neural effects, suggesting its potential as a complementary treatment to pharmacological approaches in central nervous system disorders. In this study, we utilized zebrafish to model ASD characteristics induced by VPA and hypothesized that sensory stimulation through EE could ameliorate the behavioral and neuroanatomical features associated with ASD. To test this hypothesis, we assessed social behavior, cerebellar volume, and Purkinje cell populations via histology and immunohistochemistry after exposing the fish to EE. The results revealed that zebrafish exposed to VPA exhibited social deficits, reduced cerebellar cortex volume, and a decrease in c-Fos-positive cells in the Purkinje layer. In contrast, VPA-exposed fish treated with EE showed increased socialization, augmented cerebellar cortex volume, and an elevation in c-Fos-positive Purkinje cells. These findings suggest that alterations induced by VPA may be ameliorated through EE treatment, highlighting the potential therapeutic impact of sensory stimulation in conditions related to ASD.

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“…According to previous studies, VPA suppresses cell proliferation, delays cell cycle, and induces apoptosis in vitro and in vivo (Michaelis et al 2004;Chen et al 2006;Lee et al 2014;Zhu et al 2015). Our study showed that, compared to the control, the cell proliferation in the mesenchymal compartment of the regenerated caudal fin was significantly decreased in VPA-treated zebrafish.…”

Section: Discussionmentioning

confidence: 92%

Suppressive effects of valproic acid on caudal fin regeneration in adult zebrafish

Lee

Kim

Lee

2020

Animal Cells and Systems

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Zebrafish can regenerate fins following injury through an epimorphic process that includes the formation of new tissues and reconstruction of the original morphology. In this study, the effects of valproic acid (VPA), a widely used anti-epileptic drug, on fin regeneration were studied after the caudal fin amputation of adult zebrafish. In the control group, zebrafish formed new tissues and reconstructed the original rays 14 days after amputation (dpa). Meanwhile, VPA treatments between 20 and 200 µM following amputation suppressed fin regeneration in a dose-dependent manner and altered morphological characteristics, such as bifurcation and segmentation, in the rays. Compared to the control, VPA also delayed blastema formation and decreased cell proliferation in the mesenchymal area of the regenerated fin. The mRNA expression of lef1, a downstream signaling gene in the Wnt pathway, was transiently increased in the regenerated fin of the control at 2 dpa; the same increase was not observed in the VPA-treated zebrafish. Sodium butyrate (SB), an histone deacetylase activity (HDAC) inhibitor, suppressed the fin regeneration without affecting the morphological characteristics of the regenerated ray. Furthermore, the transient increase of lef1 mRNA was not suppressed in the SB-treated zebrafish. These results suggested that VPA's suppressive effects on fin regeneration are partly mediated through decreased cell proliferation and lef1 mRNA expression.

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Valproic acid decreases cell proliferation and migration in the cerebellum of zebrafish larvae

Cited by 8 publications

References 36 publications

Folic acid supplementation rescues valproic acid‐induced developmental neurotoxicity and behavioral alterations in zebrafish embryos

Folic acid supplementation rescues valproic acid‐induced developmental neurotoxicity and behavioral alterations in zebrafish embryos

Effect of Enriched Environment on Cerebellum and Social Behavior of Valproic Zebrafish

Suppressive effects of valproic acid on caudal fin regeneration in adult zebrafish

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