Real-World Assessment of Psychotropic and Antiepileptic Drug Use During Pregnancy in Belgium: Trends, Predictors, and Comparative Risk of Congenital Anomalies (2010-2016).

PURPOSE: To analyze the prescription patterns and sociodemographic factors associated with the use of antipsychotic, antidepressant, and antiepileptic drugs during pregnancy in Belgium, and to investigate their potential association with congenital anomalies. METHODS: Using a nationwide linked database, we identified antidepressants, antipsychotics, and antiepileptics via the Anatomical Therapeutic and Chemical Classification (ATC) codes. For each medication group, we calculated the overall prevalence and prevalence for the three most used medications at the fifth ATC level. Sociodemographic factors influencing medication use during pregnancy were analyzed, and potential associations with congenital anomalies were investigated through logistic regression models based on generalized estimating equations. RESULTS: Overall, 828 016 live births pregnancies associated with 611 094 mothers were identified. We found that the use of antidepressants, antipsychotics, and antiepileptics was decreasing with the arrival of pregnancy. Mothers with a less favorable sociodemographic status were more likely to be exposed to these medications. Antiepileptics used in the first trimester were associated with an increased risk of congenital anomalies (aOR = 1.65, 95% CI 1.11-2.45) compared with unexposed women. The three most used antiepileptics were lamotrigine, valproate, and levetiracetam, among them, we found an association with congenital anomalies only for valproate (aOR = 3.92, 95% CI 2.30-6.67). CONCLUSIONS: Psychotropic and antiepileptic drug use decreased during pregnancy. Pregnant women with a less favorable sociodemographic status were more likely to be exposed to psychotropics and antiepileptics during pregnancy. The elevated risk of congenital anomalies associated with antiepileptics use, particularly valproate, underscores the need for targeted interventions and increased awareness to improve maternal and fetal health outcomes.

Cytotoxicity, genotoxicity and mutagenicity of mixed ternary mononuclear Mg complex based on valproic acid with 1,10-phenanthroline in Saccharomyces cerevisiae and V79 cells.

Valproic acid (VA) is a widely used drug for the treatment of diseases affecting the central nervous system. Due to its epigenetic modulatory potential, it has been studied for possible therapeutic application in anticancer therapies. However, the VA exhibits different side effects in its application. Thus, synthetic coordination complexes with valproate can generate promising candidates for new active drugs with reduced toxicity. In this sense, we investigated the genotoxic and mutagenic potential of the sodium valproate and of the mixed ternary mononuclear Mg complex based on VA with 1,10-phenanthroline (Phen) ligand - [Mg (Valp)2Phen], in Saccharomyces cerevisiae and V79 cells. The MTT and clonal survival assays in V79 cells indicated that the Mg complex has higher cytotoxicity than sodium valproate. A similar cytotoxicity profile is observed in yeast. This fact is possibly due to the intercalation capacity of [Mg(Valp)2Phen], inducing DNA strand breaks, as observed in the comet assay and micronucleus test. In this sense, members of the NER, HR, NHEJ and TLS repair pathways are required for the repair of DNA lesions induced by [Mg(Valp)2Phen]. Interestingly, BER proteins apparently increase the cytotoxic potential of the drug. Furthermore, the [Mg(Valp)2Phen] showed higher cytotoxicity in V79 cells and yeast when compared to sodium valproate indicating applicability as a cytotoxic agent.

A trend over time study of hepatic Farnesoid-X-activated receptor and its downstream targets modulation by valproic acid in mice.

Valproic acid (VA) is a broad-spectrum anticonvulsant agent that acts through several molecular mechanisms to control different types of seizures. The main concern of the drug is its liver toxicity. Considering the regulatory roles of the Farnesoid nuclear receptors and the nuclear transcription factor Nrf2 in modifying and neutralizing the harmful effects of oxidative damage, the present study was designed to evaluate the role of FXR-Nrf2 and some downstream target gene alterations in hepatotoxicity induced by VA. Thirty-five eight-week-old male albino mice were randomly divided into five groups, including a control group, and four groups were assigned to receive VA (300 mg/kg/day; oral) for 3, 7, 10, and 14 days. Serum levels of ALT, AST, ALP, and total and direct bilirubin (TB, DB) were measured. Liver histology and the expression of FXR, Nrf2, α-GST, SOD, and TNF-α were assessed using H&E staining and real-time RT-PCR techniques. Maximum extent of biochemical and histopathological damage was observed on the 14th day, but changes in the expression of FXR, Nrf2, α-GST, and SOD were seen at three points: a significant upregulation on the 3rd day, a remarkable downregulation on the 10th day, and a second-time upregulation on the 14th day. In conclusion, considering the observed dysregulation in FXR-Nrf2 cascade expression during VA administration, it seems that downregulation in this pathway and consequently its downstream detoxification and antioxidant genes may play a role in liver toxicity.

Understanding the impact of valproate on male fertility: insights from preclinical and clinical meta-analysis.

BACKGROUND: Valproic acid (VPA) is a widely used antiepileptic drug (AED) often prescribed as a first-line treatment for many idiopathic and symptomatic generalized epilepsies. Several studies have highlighted the side effects of VPA on male fertility and reproductive factors in males, although the specific underlying etiology of these abnormalities is not clear. The present systematic review and meta-analysis aimed to assess the preclinical and clinical evidence concerning the impact of VPA on male fertility and reproductive factors. METHODS: The scientific literature was reviewed for eligibility using PubMed, Web of Science, and PsycINFO, encompassing preclinical and clinical studies. Factors related to male fertility and reproduction, such as differences in sperm count, sperm motility, and the percentage of abnormal sperm, were compared between the experimental groups treated with VPA (in both preclinical and clinical) and the control groups using the Standardized Mean Difference (SMD) with 95% confidence intervals (CIs). Additionally, differences in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were explicitly assessed in clinical studies. RESULTS: Male fertility data were extracted from 7 preclinical studies (112 animals) and 5 clinical studies (274 male individuals). The results of animal studies found that the sperm count (SMD = -2.28, 95% CI: -3.39 to -1.18, P = 0.335) and sperm motility (SMD = -2.32, 95% CI: -3.34 to -1.30, P = 0.368) were decreased in the treated groups compared to the control groups. The percentage of abnormal sperm (SMD = 3.27, 95% CI: 1.98 to 4.56, P = 0.019) was significantly increased, while a non-significant reduction was revealed in the weight of the testis (SMD = -2.73, 95% CI: -4.23 to -1.23, P = 0.673) in treated groups. The outcomes of clinical studies indicated a non-significant decrease in sperm count (SMD = -0.78, 95% CI: -1.58 to 0.03, P = 0.286) among patients with epilepsy treated with VPA compared to control subjects. However, a significant reduction in sperm motility (SMD = -1.62, 95% CI: -2.81 to -0.43, P = 0.033 was observed. The percentage of abnormal sperm showed a non-significant increase (SMD = 0.93, 95% CI: -0.97 to 2.84, P = 0.616) after being treated with VPA. Furthermore, there was a non-significant reduction in the levels of FSH (SMD = -1.32, 95% CI: -2.93 to 0.29, P = 0.198) and LH (SMD = -0.96, 95% CI: -1.95 to 0.04, P = 0.211) observed in clinical participants. CONCLUSION: This meta-analysis of both preclinical and clinical studies revealed that VPA causes a significant reduction in male fertility and reproductive factors among male patients with epilepsy. Clinical neurologists should be more cautious when prescribing VPA, especially to young male adult patients with epilepsy.

Moringa oleifera hydroalcoholic leaf extracts mitigate valproate-induced oxidative status in the extraorbital lacrimal gland in a rat model.

Dysfunction of the extraorbital lacrimal gland (ELG) can lead to loss of vision due to damage to the epithelium of cornea. The broad-spectrum anti-epileptic drug sodium valproate (SV) has numerous side effects. Moringa oleifera (M.oleifera) is widely used as a food and in folk medicine. The effects of orally administered SV and M. oleifera hydroalcoholic leaf extract on rat ELG were investigated in this study by analysing both antioxidant and oxidant parameters. Additionally, boron level and tissue factor (TF) activity were determined. Protein changes were detected by sodium dodecyl sulfate gel electrophoresis (SDS-PAGE). Significantly lower values of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) were observed in the SV group compared to the control group. Treatment with Moringa extract significantly increased SOD, CAT and TAS values in the Moringa given SV group (SVM). While no significant differences were observed between the sialic acid values of the groups, lipid peroxidation (LPO), nitric oxide (NO) and total oxidant status (TOS) values were significantly elevated in the SV group compared to the control group. Due to the effect of Moringa extract, LPO, NO and TOS levels were significantly decreased in the SVM group compared to the SV group. TF activity was not meaningfully altered between groups. Compared to control rats, oxidative stress index (OSI) level significantly increased, whereas the boron level decreased in the SV group. Moringa extract treatment noticeably reduced OSI in the SVM group. According to SDS-PAGE, decreases in the density of protein bands with molecular weights of 51, 83, and 90 kDa were observed in SV given rats compared to the other groups. These decreases were reversed by the administration of Moringa extract. Moringa extract has shown protective properties arising from antioxidant potential, especially with its very low OSI value. Individuals undergoing SV treatment and having ELG complications might consider using Moringa extract to mitigate valproate induced damage.

Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol.

PURPOSE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.

Valproate-Autism Labyrinth.

Valproate and Autism complexity is manifold. From an established environmental risk factor for autism, to a translational animal model, valproate's composite mode of action might unfold to address core autistic domains transcending mere aggressive behavioural control.

Anxiolytic and sedative effects of sodium valproate with different experimental paradigms in male and female rats.

Valproic acid or sodium valproate is a widely used drug in the treatment of epilepsy, although it also appears to have anxiolytic and sedative properties derived from its agonistic action on the GABAergic system. To analyze these potential effects of the drug, we conducted three experiments with rats using procedures designed to assess anxiety in rodents. In the first experiment, with a fear conditioning procedure, three groups of male rats were included that received either 100 mg/kg or 300 mg/kg of valproate or an equivalent volume of saline solution. In Experiment 2, recording spontaneous activity in an open field, we compared the effects of valproic acid (300 mg/kg) on male and female rats. In the third experiment, we analyzed the effect of valproic acid using a novelty-induced hypophagia test and tested again for potential differences as a function of the sex of the animals. The results showed an anxiolytic effect restricted to the 300 mg/kg dose of the drug in Experiment 1. Such an effect was restricted to the female sample in Experiment 2, but in the third experiment affected both sexes. As for the sedative effect, it was observed in all experiments irrespective of the sex of the rats. These findings hold significant implications for the treatment of anxiety disorders since valproate may offer a novel therapeutic approach for anxiety-related conditions with distinct benefits and fewer side effects. However, clinical studies are needed to validate the translation of these findings from animal models to human patients.

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.

PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate. METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R. RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference data set of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily. CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

Therapeutic drug monitoring for valproate: deriving a novel formula for calculation of free concentration.

BACKGROUND: Monitoring free valproate concentrations, as with other highly protein-bound anticonvulsants, is essential in clinical situations where protein binding may be disrupted. Conversion of measured total concentrations to approximate free concentrations offers a cost-effective alternative. This study evaluated the relationship between total and free valproate concentrations for discordance and the impact of key determinants. A novel formula was devised that incorporates significant variables. METHODS: A multicentre, cross-sectional observational analytical study included 101 subjects 18 years and older using valproate for 6 months or longer. Participants were recruited from private and public sector healthcare settings from primary to tertiary level in, South Africa, during 2017-2019. RESULTS: Free valproate concentrations could be measured for 84 subjects. Discordance for concomitant total and free valproate concentrations was 79.1%. Among 19 participants with elevated free concentrations, 15 (78.9%) had total valproate concentrations within the recommended reference range. Calculations based on the study-derived formula were more accurate in predicting free valproate concentration than previously proposed methods. CONCLUSION: This study proposes that the novel formula for calculating free valproate enables more accurate prediction.

Is there any concern of insulin resistance and metabolic dysfunctions with antiseizure medications? A prospective comparative study of valproate vs. levetiracetam.

PURPOSE: To evaluate the incidence of insulin resistance and its association with change in serum anti-seizure medication (ASM) level and their pharmacokinetic, body composition and metabolic hormones after six months of levetiracetam (LEV) exposure in persons with epilepsy (PWE) in comparison to valproate (VPA). METHODS: This prospective-longitudinal study included clinically diagnosed PWE on VPA or LEV monotherapy (for<3 months). At enrolment, body weight/composition, BMI were measured and blood samples were collected for assessing metabolic dysfunctions by estimation of serum insulin, insulin resistance [in terms of Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)], leptin, adiponectin, lipid profile along with ASMs level. Subjects were followed up for six months and all the above parameters were reassessed. RESULTS: A total of 150 PWE were screened based on inclusion and exclusion criteria, and 105 number of subjects were enrolled (n = 35 in VPA and n = 70 in LEV group). Out of them, 92 subjects (n = 32 in VPA; n = 60 in LEV) completed six months follow-up. After six months, serum insulin level increased significantly in VPA group compared to baseline p < 0.001). Insulin resistance (HOMA-IR>2.5) was observed in 14.28 % of PWE in VPA group. Significantly higher percentage-change in body-weight (p = 0.003), leptin and decreased adiponectin were found in VPA-group compared to baseline ((p = 0.003, 0.02, 0.001, <0.001, respectively). These changes were independent of serum level or pharmacokinetic of VPA. On the other hand, no such changes were observed in LEV-group despite increased serum LEV level and altered pharmacokinetic parameters after six months. CONCLUSION: Six months treatment with VPA resulted in insulin resistance and metabolic dysfunctions in PWE. These alterations were not correlated with change in VPA serum level. These changes were not observed in LEV therapy suggesting its better safety profile. This may be considered while prescribing the ASM like VPA and LEV in adult patients with obesity or insulin resistance and diabetes.

Sodium Valproate-Induced Hyperammonemia: A Case Series in a Tertiary Care Hospital.

BACKGROUND: Sodium valproate (VPA) is an extensively used anti-convulsant, which is an effective drug for treatment of epilepsy in adults and children, as well as for conditions like migraine, bipolar disorder, mania, and trigeminal neuralgia. Sedation, vertigo, ataxia, dose-dependent tremors, headaches, and gastrointestinal side effects are the most often reported adverse effects associated with VPA. A potential life-threatening event reported with VPA is hyperammonemia (HA), which is defined as an increase in serum level of ammonia. Only 587 reported cases of HA were found in the VigiAccess database, representing a mere 0.6% of the 95,000 reported adverse events linked to VPA. Hence, this case series was conducted with emphasis on monitoring of increased serum ammonia levels with or without hepatic enzymes increase for patients who are on VPA. AIMS AND OBJECTIVES: To assess elevated serum ammonia levels following VPA administration, and to ascertain the percentage of individuals with hepatic enzymes increased who took VPA and subsequently had elevated serum ammonia levels. METHODS: This study was conducted at the adverse drug reaction (ADR) monitoring centre (AMC) of the Pharmacovigilance Programme of India (PvPI) and Department of Psychiatry, Christian Medical College and Hospital (CMC&H), Ludhiana. The study comprised of 12 patients who were exclusively on VPA and exhibited symptoms related to elevated serum ammonia. An informed consent form (ICF) was provided to the patient prior to taking their personal details. Laboratory investigations were done to establish the diagnosis and liver function tests (LFTs), chiefly ALT (alanine transferase) and AST (aspartate aminotransferase) were also performed. It is a descriptive study which was for a time period of six months.  Results: This study includes 12 patients who had HA confirmed by laboratory investigation. Out of these 12 patients, two patients (17%) had a corresponding increase in LFT. The average as of the patients was 53.08 years and average serum ammonia levels were 219.15. None of the patients who presented with HA progressed to hyperammonemic encephalopathy (HAE). CONCLUSION:  This case series on valproate-induced HA should be of interest to psychiatrists, physicians, internists, family medicine physicians, hospitalists, and surgeons who will have patients on VPA. Delay in recognition of HA can result in the development of potentially life-threatening complications. Rapid diagnosis and management will help in reducing the number of cases which progress to encephalopathy which is highly fatal.

Delving into the Complexity of Valproate-Induced Autism Spectrum Disorder: The Use of Zebrafish Models.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition with several identified risk factors, both genetic and non-genetic. Among these, prenatal exposure to valproic acid (VPA) has been extensively associated with the development of the disorder. The zebrafish, a cost- and time-effective model, is useful for studying ASD features. Using validated VPA-induced ASD zebrafish models, we aimed to provide new insights into VPA exposure effects during embryonic development and to identify new potential biomarkers associated with ASD-like features. Dose-response analyses were performed in vivo to study larval phenotypes and mechanisms underlying neuroinflammation, mitochondrial dysfunction, oxidative stress, microglial cell status, and motor behaviour. Wild-type and transgenic Tg(mpeg1:EGFP) zebrafish were water-exposed to VPA doses (5 to 500 µM) from 6 to 120 h post-fertilisation (hpf). Embryos and larvae were monitored daily to assess survival and hatching rates, and numerous analyses and tests were conducted from 24 to 120 hpf. VPA doses higher than 50 µM worsened survival and hatching rates, while doses of 25 µM or more altered morphology, microglial status, and larval behaviours. VPA 50 µM also affected mRNA expression of inflammatory cytokines and neurogenesis-related genes, mitochondrial respiration, and reactive oxygen species accumulation. The study confirmed that VPA alters brain homeostasis, synaptic interconnections, and neurogenesis-related signalling pathways, contributing to ASD aetiopathogenesis. Further studies are essential to identify novel ASD biomarkers for developing new drug targets and tailored therapeutic interventions for ASD.

Paternal Valproate Treatment and Risk of Childhood Neurodevelopmental Disorders: Precautionary Regulatory Measures Are Insufficiently Substantiated.

On January 12, 2024 the safety committee of the European Medicines Agency (EMA) recommended precautionary measures over a potential risk of neurodevelopmental disorders in children born to men treated with valproate. These new measures recommend patient supervision by a specialist in the management of epilepsy, bipolar disorder, or migraine. In the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) issued a far more stringent precaution, warning against prescribing valproate to anyone under 55 years of age. We, members of the European Network of Teratology Information Services (ENTIS) and the Organization of Teratology Information Specialists (OTIS), believe that the EMA and MHRA warnings were premature. We are of the opinion that the underlying scientific data do not convincingly substantiate the inference of a paternally mediated risk from valproate to children, much less to an extent that justifies these far-reaching recommendations.

Facial dysmorphism and Limb abnormalities of Fetal Valproate Syndrome.

A neonate born to nonconsanguineous parents was evaluated for dysmorphic features. The neonate was born at term by normal vaginal delivery. The mother has had epilepsy for 12 years and has been on sodium valproate (700 mg/day) since conception and throughout pregnancy. Examination revealed facial dysmorphism, including triangular forehead, sparse arched eyebrows, telecanthus, flat nasal bridge, long thin upper vermilion border, smooth philtrum, and low-set ears. The limb anomalies observed were arachnodactyly, wrist and elbow contractures, clinodactyly, hypoplastic toenails, and overlapping toes. The other dysmorphisms noted were widely spaced nipples and hypospadias. Ultrasonogram (USG) cranium showed bilateral choroid plexus cysts, and USG abdomen revealed bilateral mild hydronephrosis. 2D-Echocardiography revealed a small patent ductus arteriosus (PDA). A diagnosis of fetal valproate syndrome (FVS) was considered, and other differentials, including fetal alcohol syndrome and genetic conditions, were ruled out by a clinical geneticist review. The index neonate is currently on multidisciplinary follow-up. The index neonate had common features of FVS as described in the literature, in addition to wrist and elbow contractures. Apart from the anomalies, there is a significant risk for neurocognitive delay and neurodevelopmental disorders. Postnatally, these babies need multidisciplinary care and neurodevelopmental follow-up. Valproate use for treating epilepsy in pregnant women and women of childbearing age may be restricted, and alternative choices of ASMs with better safety profiles should be preferred. Facial dysmorphism and limb anomalies in fetal valproate syndrome may occur irrespective of the dose of sodium valproate. Fetal valproate syndrome may present with wrist and elbow contractures.

Ferroptosis promotes valproate-induced liver steatosis in vitro and in vivo.

Valproic acid (VPA), a common antiepileptic drug, can cause liver steatosis after long-term therapy. However, an impact of ferroptosis on VPA-induced liver steatosis has not been investigated. In the study, treatment with VPA promoted ferroptosis in the livers of mice by elevating ferrous iron (Fe2+) levels derived from the increased absorption by transferrin receptor 1 (TFR1) and the decreased storage by ferritin (FTH1 and FTL), disrupting the redox balance via reduced levels of solute carrier family 7 member 11 (SLC7A11), glutathione (GSH), and glutathione peroxidase 4 (GPX4), and augmenting acyl-CoA synthetase long-chain family member 4 (ACSL4) -mediated lipid peroxide generation, accompanied by enhanced liver steatosis. All the changes were significantly reversed by co-treatment with an iron-chelating agent, deferoxamine mesylate (DFO) and a ferroptosis inhibitor, ferrostatin-1 (Fer-1). Similarly, the increases in Fe2+, TFR1, and ACSL4 levels, as well as the decreases in GSH, GPX4, and ferroportin (FPN) levels, were detected in VPA-treated HepG2 cells. These changes were also attenuated after co-treatment with Fer-1. It demonstrates that ferroptosis promotes VPA-induced liver steatosis through iron overload, inhibition of the GSH-GPX4 axis, and upregulation of ACSL4. It offers a potential therapy targeting ferroptosis for patients with liver steatosis following VPA treatment.

Acetyl-l-carnitine alleviates valproate-induced autism-like behaviors through attenuation of hippocampal mitochondrial dysregulation.

This study aimed to evaluate the potential benefits of acetyl-L-carnitine (ALCAR) in the context of valproate-induced autism. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p.) on embryonic day 12.5, followed by ALCAR treatment (300 mg/kg on postnatal days 21-49, p.o.), assessment of oxidative stress, mitochondrial membrane potential (MMP), mitochondrial biogenesis, parvalbumin interneurons, and hippocampal volume was conducted. These assessments were carried out subsequent to the evaluation of autism-like behaviors. Hippocampal analysis of oxidative factors (reactive oxygen species and malondialdehyde) and antioxidants (superoxide dismutase, catalase, and glutathione) revealed a burden of oxidative stress in VPA rats. Additionally, mitochondrial biogenesis and MMP were elevated, while the number of parvalbumin interneurons decreased. These changes were accompanied by autism-like behaviors observed in the three-chamber maze, marble burring test, and Y-maze, as well as a learning deficit in the Barnes maze. In contrast, administrating ALCAR attenuated behavioral deficits, reduced oxidative stress, improved parvalbumin-positive neuronal population, and properly modified MMP and mitochondrial biogenesis. Collectively, our results indicate that oral administration of ALCAR ameliorates autism-like behaviors, partly through its targeting oxidative stress and mitochondrial biogenesis. This suggests that ALCAR may have potential benefits ASD managing.

Unexpected Cataract Formation Following Valproate Treatment: A Case Report.

Valproic acid (VPA), or sodium valproate, is a frequently prescribed medication for many psychiatric conditions, notably for the management of bipolar affective disorder. While its common side effects are well known and thoroughly documented in medical literature, the occurrence of cataracts as a side effect is exceedingly rare. There is evidence of cataract formation with long-term use of VPA in a few studies. Recognizing this potential adverse effect is crucial. It is important to recommend that patients undergo regular eye examinations if they experience any visual disturbances or as a preventative measure to ensure effective management. This case report examines the unusual occurrence of cataract development associated with valproate use.