Sodium Valproate Exposure Research Articles

Sodium valproate exposure influences the expression of pparg in the zebrafish model.

Valproic acid (VPA) is an anti-epileptic drug used alone or in combination with other medications to treat seizures, mania, and bipolar disorder. VPA recognized as a teratogenic chemical can cause severe birth defects mainly affecting the brain and spinal cord when administered during pregnancy. However, the potential mechanisms of developmental toxicity are still less studied, and in the present study, the influence of VPA exposure was evaluated on zebrafish early-life stages. Zebrafish were exposed to two sublethal concentrations of sodium valproate (SV) (0.06 mM and 0.15 mM) from 24 hours post-fertilization (hpf) to 96 hpf and the SV teratogenic potential was investigated through morphometric analysis of zebrafish larvae combined with the evaluation of cartilage profile. Moreover, the effect of SV on the transcription level of pparg was also performed. The results of the study showed the teratogenic potential of SV, which disrupts the morphometric signature of the head and body. The marked distortion of cartilage structures was paralleled to a malformation of telencephalon and optic tectum in both concentrations suggesting a high teratogen effect of SV on the brain. These data were further confirmed by the increased expression of pparg in the zebrafish head. Overall, the present study confirms the teratogenic activity of SV in the zebrafish model and, for the first time, points out the potential protective role of pparg in the SV dose-dependent toxicity.

Effects of sodium valproate exposure during gestational period on offspring’s secretion function of cortisol in common marmosets

Effects of sodium valproate exposure during gestational period on offspring’s secretion function of cortisol in common marmosets

The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs.

A number of antiepileptic drugs (AEDs) have been confirmed as teratogens due to their association with an increased malformation rate. The majority of research to date does not find an association between prenatal exposure to monotherapy carbamazepine, lamotrigine or phenytoin and neurodevelopmental outcome in comparison to control children and noted higher abilities in comparison to children exposed to valproate; but further work is needed before conclusions can be drawn. Data for levetiracetam was limited to one study, as was the evidence for topiramate. Sodium valproate exposure appeared to carry a dose dependent risk to the developing brain, with evidence of reduced levels of IQ, poorer verbal abilities and increased rate of autistic spectrum disorder both in comparison to control children and children exposed to other AEDs. The severity of the neurodevelopmental deficits associated with prenatal exposure to valproate highlight the critical need to consider neurodevelopmental outcomes as a central aspect of teratological research.

Neurobehavioural effects of prenatal sodium valproate exposure in rat offspring

Pregnant rats were administered sodium valproate (12.5, 25 and 50 mg/kg/day) orally once daily during the gestation days 13 to 20. Maternal sodium valproate treatment produced a dose dependent significant reduction in litter size at birth and reduced body growth during postnatal days. Sodium valproate treatment had no significant effect on maternal weight gain during pregnancy and pups mortality during postnatal period. The pups born were subjected to open-field exploratory behaviour and elevated plus maze tests of anxiety at 8 and 9 weeks of age. Prenatal sodium valproate treatment (12.5, 25 and 50 mg/kg/day) induced significant increase in open-field ambulation, rearings and self-grooming in rat offspring. Prenatal sodium valproate treated rat offspring displayed significantly increased anxiogenic behaviour on elevated plus maze (spent less time on open arms, more time on enclosed arms and made fewer number of entries on open arms) comparison to control rat offspring. The results suggest that prenatal sodium valproate exposure induces neurobehavioural toxicity and indicate persistent behavioural alterations in the rat offspring.

Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy.

The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.

Effects of sodium valproate exposure during gestational period on social skills in common marmosets (Callithrix jacchus)

Effects of sodium valproate exposure during gestational period on social skills in common marmosets (Callithrix jacchus)

Altered cortical thickness following prenatal sodium valproate exposure.

Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children.

Is sodium valproate, an HDAC inhibitor, associated with reduced risk of stroke and myocardial infarction? A nested case-control study.

BackgroundThis study aimed to evaluate whether treatment with sodium valproate (SV) was associated with reduced risk of stroke or myocardial infarction (MI).MethodsElectronic health records data were extracted from Clinical Practice Research Database for participants ever diagnosed with epilepsy and prescribed antiepileptic drugs. A nested case–control study was implemented with cases diagnosed with incident non-haemorrhagic stroke and controls matched for sex, year of birth, and study start date (ratio of 1:6). A second nested study was implemented with MI as outcome. The main exposure variable was SV therapy assessed as: ever prescribed, pre-stroke year treatment, number of SV prescriptions, and cumulative time on SV drug therapy. Odds ratios were estimated using conditional logistic regression.ResultsData were analysed for 2002 stroke cases and 13 098 controls. MI analyses included 1153 cases and 7109 controls. Pre-year stroke SV treatment (28%) was associated with increased stroke risk (odds ratio 1.22, 95% confidence interval (CI): 1.09 to 1.38, p < 0.001). No association was observed between ever being prescribed SV with ischemic stroke (OR = 1.01, 95% CI: 0.91 to 1.12, p = 0.875). A significant association was observed between ever being prescribed SV with MI (OR = 0.78, 95% CI: 0.67 to 0.90, p < 0.001). Patients in the highest quarter of SV treatment duration had lower odds of ischemic stroke (OR = 0.57, 95% CI: 0.44 to 0.72, p < 0.001) and MI (OR = 0.29, 95% CI: 0.20 to 0.44, p < 0.001).ConclusionSodium valproate exposure was associated with the risk of MI, but not ischemic stroke. However, longer exposure to SV was associated with lower odds of stroke, but this might be explained by survivor bias.

Sodium valproate exposure during the brain growth spurt transiently impairs spatial learning in prepubertal rats

The brain is extremely vulnerable to teratogenic insults during the brain growth spurt, a period that starts during the third trimester of human gestation and is characterized by synaptogenesis establishment of neuronal circuits. While the treatment of epilepsy during pregnancy increases the risk of neurodevelopmental disorders in offspring, the consequences of exposure to anticonvulsants during the brain growth spurt remain poorly known. Here we investigate whether exposure to sodium valproate (VPA) during a similar period in rats impairs spatial learning of juvenile rats. Long-Evans rats were exposed to VPA (200mg/kg) or saline solution (SAL) every other day between postnatal day (PN) 4 and PN10. At PN23 and PN30, Morris water maze performance was evaluated during 6 consecutive days. In the group of animals which started their tests at PN23, the VPA exposure impaired both, swimming speed and learning/memory performance. Interestingly, no differences were observed between VPA and control animals tested from PN30 to PN35. Our data suggests that the neurobehavioral deficits caused by VPA exposure during the brain growth spurt are transitory.

Early cognitive development in children born to women with epilepsy: A prospective report

In this prospective study the early cognitive development of children born to women with epilepsy (n = 198) was assessed and compared to a group of children representative of the general population (n = 230). The children were assessed when younger than the age of 2 years using the Griffiths Mental Development Scales, either in their local participating hospital or in their home. The assessments were completed by an assessor who was blinded to whether the child's mother had epilepsy and to antiepileptic drug type. Children exposed to sodium valproate had a statistically significant increased risk of delayed early development in comparison to the control children. Linear regression analysis showed a statistically significant effect of sodium valproate exposure on the child's overall developmental level that was not accounted for by confounding variables. Delayed early development is also noted for children within an ad hoc group of less commonly utilized antiepileptic drugs, although conclusions cannot be drawn due to the size of this group (n = 13). Children exposed to either carbamazepine or lamotrigine in utero did not differ significantly in their overall developmental ability. Differences noted in specific developmental areas for these two groups were not statistically significant after the control for confounders such as socioeconomic status and maternal IQ. Women with epilepsy should be informed of the risks posed to their potential offspring prior to pregnancy to allow for informed decisions regarding treatment. Children exposed in utero to antiepileptic drugs should be monitored throughout childhood to allow for early intervention when necessary.

De Novo Mutations in POLG Presenting with Acute Liver Failure or Encephalopathy

De Novo Mutations in <i>POLG</i> Presenting with Acute Liver Failure or Encephalopathy

Sodium Valproate Exposure In Utero Linked to Autism Risk

Sodium Valproate Exposure In Utero Linked to Autism Risk

Anatomical and Behavioral Effects of in Utero Exposure to Antiepileptic Drugs

Anatomical and Behavioral Effects of in Utero Exposure to Antiepileptic Drugs

Fetal exposure to sodium valproate associated with Baller–Gerold syndrome: case report and review of the literature

We report three patients with a history of maternal valproate use during pregnancy who presented with a combination of metopic suture synostosis and upper limb malformations, which could be diagnosed as Baller-Gerold syndrome (BGS). The patients underwent surgical treatment for the craniofacial deformity, during which standard frontocranial reconstruction was performed. Only 32 patients have been reported in the world literature and these cases support the emerging view that BGS is not a distinct syndrome, but should instead be considered to be an heterogeneous phenotype with variable etiology. Our case series suggests for the first time that fetal sodium valproate exposure may also cause this phenotype.

Neuropsychological effects of exposure to anticonvulsant medication in utero

To investigate the long-term differential drug effects on cognitive functioning in school-aged children exposed to antiepileptic drugs (AEDs) in utero. Mothers with epilepsy were recruited from specialist epilepsy clinics and obstetric clinics from the Liverpool and Manchester region. The mothers and their children were recruited without prior knowledge of their AED treatment during pregnancy or the health of the offspring. A battery of neuropsychological tests was applied to each mother-child pair in order to obtain a neuropsychological profile for each child. Neuropsychological investigation was performed on 249 children between the ages of 6 and 16. Children exposed to sodium valproate had a significantly lower verbal IQ when compared to children exposed to other antiepileptic drugs or not exposed at all. The same children were more likely to have an IQ below 69 and more likely to have memory impairment when compared to the other groups. The mothers' IQ, exposure to sodium valproate, and the number of tonic-clonic seizures during pregnancy were significant predictors of verbal IQ in this population. This retrospective study highlights the potential harmful effects of sodium valproate exposure in utero on neuropsychological development.

The influence of developmental periods of sodium valproate exposure on synaptic plasticity in the CA1 region of rat hippocampus

The effects of chronic sodium valproate (VPA) exposure during different developmental periods on synaptic plasticity were studied in the hippocampal CA1 area. Rats were exposed to VPA (300 mg/kg per day, intraperitoneal) over different developmental intervals: (1) prenatal exposure (PR group); (2) from parturition to weaning (PW group); (3) from pregnancy day 1 to weaning (PRW group). At postnatal day 22–28, field excitatory postsynaptic potentials were recorded in the CA1 area of hippocampal slices. We found that VPA exposure in the PR and PRW groups significantly impaired long-term potentiation (LTP), long-term depression (LTD) and paired-pulse facilitation (PPF). However, exposure during lactation (PW group) only impaired LTP and had no significant effect on LTD and PPF. These results suggested that VPA exposure during lactation had the least deficits on synaptic plasticity, while VPA exposure in the PR and PRW groups seriously impaired synaptic plasticity and should be avoided.

The influence of developmental periods of sodium valproate exposure on synaptic plasticity in the CA1 region of rat hippocampus

The effects of chronic sodium valproate (VPA) exposure during different developmental periods on synaptic plasticity were studied in the hippocampal CA1 area. Rats were exposed to VPA (300 mg/kg per day, intraperitoneal) over different developmental intervals: (1) prenatal exposure (PR group); (2) from parturition to weaning (PW group); (3) from pregnancy day 1 to weaning (PRW group). At postnatal day 22–28, field excitatory postsynaptic potentials were recorded in the CA1 area of hippocampal slices. We found that VPA exposure in the PR and PRW groups significantly impaired long-term potentiation (LTP), long-term depression (LTD) and paired-pulse facilitation (PPF). However, exposure during lactation (PW group) only impaired LTP and had no significant effect on LTD and PPF. These results suggested that VPA exposure during lactation had the least deficits on synaptic plasticity, while VPA exposure in the PR and PRW groups seriously impaired synaptic plasticity and should be avoided.

Sodium valproate induces apoptosis in the rat hepatoma cell line, FaO.

Sodium valproate (VPA) is clinically employed as an anti-convulsant and, to a lesser extent, mood stabilizer. While the incidence of toxicity associated with the clinical use of valproate is low, serious hepatotoxicity makes up a significant percentage. Rats treated with high doses of sodium valproate are subject to hepatotoxicity, and the study of the molecular mechanisms underlying this phenomenon may shed further light on the human situation. Exposure to sodium valproate results in the down regulation in rat liver of several transcripts whose products are involved in cellular energy homeostasis, resulting in time-dependent fluctuations in cellular ATP, possibly resulting in cell death. To further examine this, classical markers of apoptosis were examined in the rat hepatoma cell line FaO following sodium valproate exposure. Concentrations greater than 300 microM sodium valproate resulted in a transient wave of apoptosis, as assessed by chromatin condensation and DNA fragmentation assay. Analysis indicated that Fas-ligand and caspase-11 expression were increased at the transcriptome level, while caspase-3 was activated at the proteome level during the exposure period. These data demonstrates that sodium valproate causes cell death through apoptosis in a rat liver cell line, and provides information on the possible molecular mechanisms underlying this phenomenon in vivo.