Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid

Shona, S I; Rizk, A.; Sadik, Abir El; Emam, H.; Ali, Eid N.

doi:10.5603/fm.a2017.0100

Cited by 19 publications

(26 citation statements)

References 24 publications

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“…In folate‐deficient models, FA supplementation partially reverses zebrafish neural tube 28 and rat brain defects 26 . Additionally, FA protects against VPA‐induced neural tube and brain defects in mice 25 and rats 39 . Together these reports emphasize the important function of FA for normal neurodevelopment.…”

Section: Discussionmentioning

confidence: 84%

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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: Discussionmentioning

confidence: 84%

“…26 Additionally, FA protects against VPA-induced neural tube and brain defects in mice 25 and rats. 39 Together these reports emphasize the important function of FA for normal neurodevelopment. Concordantly, we showed that FA supplementation protects against VPA-induced reduced midbrain size and hindbrain midline gap defects.…”

Section: F I G U R Ementioning

confidence: 89%

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

et al. 2021

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“…Therefore, if the epigenetic diet is a promising avenue for migraine treatment, studies on diets fortified with VPA should be undertaken. Notably, VPA has teratogenic potential and folate is speculated to act protectively against the side effects of VPA, although some results are contradictory [120,121,122].…”

Section: Discussionmentioning

confidence: 99%

Is an “Epigenetic Diet” for Migraines Justified? The Case of Folate and DNA Methylation

Fila

Chojnacki

et al. 2019

Nutrients

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Migraines are a common disease with limited treatment options and some dietary factors are recognized to trigger headaches. Although migraine pathogenesis is not completely known, aberrant DNA methylation has been reported to be associated with its occurrence. Folate, an essential micronutrient involved in one-carbon metabolism and DNA methylation, was shown to have beneficial effects on migraines. Moreover, the variability of the methylenetetrahydrofolate reductase gene, important in both folate metabolism and migraine pathogenesis, modulates the beneficial effects of folate for migraines. Therefore, migraine could be targeted by a folate-rich, DNA methylation-directed diet, but there are no data showing that beneficial effects of folate consumption result from its epigenetic action. Furthermore, contrary to epigenetic drugs, epigenetic diets contain many compounds, some yet unidentified, with poorly known or completely unknown potential to interfere with the epigenetic action of the main dietary components. The application of epigenetic diets for migraines and other diseases requires its personalization to the epigenetic profile of a patient, which is largely unknown. Results obtained so far do not warrant the recommendation of any epigenetic diet as effective in migraine prevention and therapy. Further studies including a folate-rich diet fortified with valproic acid, another modifier of epigenetic profile effective in migraine prophylaxis, may help to clarify this issue.

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“…Blocking DHFR function by administration of the folate analogue and DHFR antagonist methotrexate (MTX) leads to neurotoxic effects in the cerebellum of newborn rats [54] as well as to the degeneration of PCs in guinea pigs, which could be rescued by application of the tetrahydrofolate derivative leucovorin [55]. This rescue effect of folate is also apparent in newborn rats, in which PC atrophy and cerebellar degenerative changes induced by treatment with valproic acid in the mothers could be markedly reduced by an additional treatment with folic acid [56]. Conceivably, an impaired DHFR function may contribute to impaired cerebellar function.…”

Section: Discussionmentioning

confidence: 99%

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study

et al. 2020

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Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10 −8 ) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10 −05 ) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

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Effect of valproic acid administration during pregnancy on postnatal development of cerebellar cortex and the possible protective role of folic acid

Abstract: The present study confirmed the protective role of folic acid against the cerebellar neurotoxic effects of VPA prenatal exposure. It is recommended that folic acid supplements should be given to every epileptic pregnant mother treated with VPA. (Folia Morphol 2018; 77, 2: 201-209).

Cited by 19 publications

References 24 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

Is an “Epigenetic Diet” for Migraines Justified? The Case of Folate and DNA Methylation

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study

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