Valproic Acid Causes Redox-Regulated Post-Translational Protein Modifications That Are Dependent upon P19 Cellular Differentiation States.

Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted. We hypothesize that VPA causes redox-sensitive post-translational protein modifications that are dependent upon cellular differentiation states. Undifferentiated P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, prior to VPA exposure. Undifferentiated cells treated with VPA alone exhibited an oxidized glutathione redox couple and increased overall protein oxidation, whereas differentiated neurons were protected from protein oxidation via increased S-glutathionylation. Pretreatment with D3T prevented the effects of VPA exposure in undifferentiated cells. Taken together, our findings support redox-sensitive post-translational protein alterations in undifferentiated cells as a mechanism of VPA-induced developmental toxicity and propose NRF2 activation as a means to preserve proper neurogenesis.

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates.

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was partially reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals' USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions.

Molecular insights into enriched environments and behavioral improvements in autism: a systematic review and meta-analysis.

Aims: Autism is a multifaceted developmental disorder of the nervous system, that necessitates novel therapeutic approaches beyond traditional medications and psychosomatic therapy, such as appropriate sensory integration training. This systematic mapping review aims to synthesize existing knowledge on enriching environmental interventions as an alternative avenue for improving autism, guiding future research and practice. Method: A comprehensive search using the terms ASD and Enriched Environment was conducted across PubMed, EMBASE, ISI, Cochrane, and OVID databases. Most of the literature included in this review was derived from animal model experiments, with a particular focus on assessing the effect of EE on autism-like behavior, along with related pathways and molecular mechanisms. Following extensive group discussion and screening, a total of 19 studies were included for analysis. Results: Enriched environmental interventions exhibited the potential to induce both behavioral and biochemical changes, ameliorating autism-like behaviors in animal models. These improvements were attributed to the targeting of BDNF-related pathways, enhanced neurogenesis, and the regulation of glial inflammation. Conclusion: This paper underscores the positive impact of enriched environmental interventions on autism through a review of existing literature. The findings contribute to a deeper understanding of the underlying brain mechanisms associated with this intervention.

Exposure to Valproic acid (VPA) resulted in alterations in the expression of angiogenic genes (NRP-1, VEGFA, VEGFR-2 and sFlt1) and histological modifications in the placenta of mice (Mus musculus).

Valproic acid (VPA), an anti-epileptic drug (AED), has been reported to exhibit anti-angiogenic properties. This study aimed to examine the impact of VPA on the expression of NRP-1 and additional angiogenic factors, as well as angiogenesis, in mouse placenta. Pregnant mice were divided into four groups: control (K), solvent control (KP), VPA treatment at a dose of 400 mg/kg body weight (BW) (P1), and VPA treatment at a dose of 600 mg/kg BW (P2). The mice were subjected to daily treatment via gavage from embryonic day (E) 9 to E14 and E9 to E16. Histological analysis was performed to evaluate Microvascular Density (MVD) and percentage of the placental labyrinth area. In addition, a comparative analysis of Neuropilin-1 (NRP-1), vascular endothelial growth factor (VEGFA), vascular endothelial growth factor receptor (VEGFR-2), and soluble (sFlt1) expression was conducted in relation to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The results of the MVD analysis and percentage of labyrinth area in the E14 and E16 placentas indicated that the treated groups were significantly lower than the control group. The relative expression levels of NRP-1, VEGFA, and VEGFR-2 in the treated groups were lower than those in the control group at E14 and E16. Meanwhile, the relative expression of sFlt1 in the treated groups at E16 was significantly higher than in the control group. Changes in the relative expression of these genes inhibit angiogenesis regulation in the mouse placenta, as evidenced by reduced MVD and a smaller percentage of the labyrinth area.

Effects of dosage in new users of lamotrigine inducing epidermal necrolysis: Results of the German Registry of Severe Skin Reactions.

OBJECTIVE: This study was undertaken to determine the impact of dosage in new users of lamotrigine (LTG) and the concomitant intake of valproic acid (VPA) on epidermal necrolysis (EN). METHODS: A total of 102 EN cases with exposure to LTG were identified (1992-2018) in the German Registry of Severe Skin Reactions. All cases are validated by an independent expert committee. Six cases were excluded due to lack of exposure in the relevant time frame. Causality assessment was performed with ALDEN (Algorithm for Assessment of Drug Causality in EN) on definite/probable cases (≥12 years; n = 84). Evaluation of dosing regimen was restricted to cases with complete LTG dosing history (n = 74). RESULTS: Demography showed a mean age of 42.4 years, female predominance (69%), and low mortality (7.3%). Epilepsy was the indication for use in 87.5%. LTG was the very probable cause in 71.4% and probable cause in 28.6%. On average, one additional antiseizure medication was taken, most frequently VPA (43/84). Combined LTG/VPA treatment showed no statistically significant difference in morbidity or mortality. Mean time latency from initiation of LTG to reaction onset was 24.2 days, varying between 21 days with high initial dose and 29.2 days with low initial dose. Low initial LTG dose (n = 9) revealed higher mortality (22.2%) and higher severity (5/9) than high initial dose (n = 35, mortality = 14.3%, 14/35 higher severity). No patient died when the starting dose was as recommended. The highest mortality (25%) was found in patients with no dose increase (n = 8), which correlated with higher age. Despite the recommended or low initial dose, 52.7% of patients developed EN, in contrast to 39.2% with a slow, recommended, or no dose escalation. SIGNIFICANCE: Neither the initial dose, dose escalation, nor the combination with VPA seems to influence the general occurrence of EN. However, EN patients with the recommended starting dose and the recommended dose escalation had the best outcome in terms of clinical severity and mortality.

Alterations in Cerebellar Microtubule Cytoskeletal Network in a ValproicAcid-Induced Rat Model of Autism Spectrum Disorders.

Autism spectrum disorders (ASD) are neurodevelopmental diseases characterised by deficits in social communication, restricted interests, and repetitive behaviours. The growing body of evidence points to a role for cerebellar changes in ASD pathology. Some of the findings suggest that not only motor problems but also social deficits, repetitive behaviours, and mental inflexibility associated with ASD are connected with damage to the cerebellum. However, the understanding of this brain structure's functions in ASD pathology needs future investigations. Therefore, in this study, we generated a rodent model of ASD through a single prenatal administration of valproic acid (VPA) into pregnant rats, followed by cerebellar morphological studies of the offspring, focusing on the alterations of key cytoskeletal elements. The expression (Western blot) of α/ß-tubulin and the major neuronal MT-associated proteins (MAP) such as MAP-Tau and MAP1B, MAP2, MAP6 (STOP) along with actin-crosslinking αII-spectrin and neurofilament light polypeptide (NF-L) was investigated. We found that maternal exposure to VPA induces a significant decrease in the protein levels of α/ß-tubulin, MAP-Tau, MAP1B, MAP2, and αII-spectrin. Moreover, excessive MAP-Tau phosphorylation at (Ser396) along with key Tau-kinases activation was indicated. Immunohistochemical staining showed chromatolysis in the cerebellum of autistic-like rats and loss of Purkinje cells shedding light on one of the possible molecular mechanisms underpinning neuroplasticity alterations in the ASD brain.

Clinical and electroencephalographic features of epilepsy in patients with triple X syndrome: A case series.

PURPOSE: Triple X syndrome, is an often undiagnosed chromosomal abnormality with an incidence of 1/1000 females. Main associated disorders are urogenital malformations, premature ovarian failure or primary amenorrhea, gastrointestinal problems, psychiatric disorders and epilepsy. To date, triple X is not related to a specific epileptic syndrome. Therefore, the purpose of this clinical series is to analyze seizure semiology, electroencephalogram features and the long-term outcome of 13 patients with epilepsy and triple X syndrome. METHODS: We retrospectively evaluated the long-term seizure outcome in patients with triple X syndrome who had been referred to 11 Epilepsy Centers in Italy. A close electroclinical follow-up was made for at least 2 years and outcomes were reported. RESULTS: Our case series confirms that epilepsy is not an occasional finding but part of the phenotypic spectrum of this syndrome. The seizure semiology shows an higher prevalence of focal seizures in 62% of patients. EEG findings of focal epileptic activity were reported in 85% of patients. Anti-seizure medications were successful in all our patients whom in most cases were responsive to monotherapy. CONCLUSION: According to our case series most successful drugs were VPA and LEV. Long term prognosis of epilepsy in our case series was good. Our experience suggests that all triple X patients achieve good seizure control and in 69% of cases normalization of the EEG.

Changes of cerebellar cortex in a valproic acid-induced rat model of autism.

In this study, 32 male Sprague-Dawley rats (8 for each group) were used in total to examine the effects of valproic acid on rat cerebellum. It was determined that the experimental group received valproic acid (600 mg/kg) on embryonic day 15 and postnatal day 11, whereas the control group was treated with saline on the same days. Moreover, on the postnatal 30th day, the cerebellums of all pups were removed and prepared for light and electron microscopy. The numerical density of granule cells in the cerebellum of experimental groups of rats increased, whereas the numerical density of Purkinje cells decreased. Furthermore, the granule cells had a smaller mean nuclear diameter in one of the experimental groups, while the Purkinje cells had in both experimental groups than those in the comparison group. Thus, the numerical density of synaptic disks and their mean diameter in the cerebellar granular layer of experimental groups were significantly decreased compared to the corresponding controls; also, the synapse-to-neurons ratio, a parameter indicating interneural connectivity, was the same. Consequently, it was seen that valproic acid administration to pups in prenatal or early postnatal days causes changes in number of neurons and synapses in the cerebellum of rats.

TCHis mitigate oxidative stress and improve abnormal behavior in a prenatal valproic acid-exposed rat model of autism.

Troxerutin is known for its anti-inflammatory and antioxidative effects in nerve impairment. The purpose of this study is to investigate the effect of troxerutin and cerebroprotein hydrolysate injections (TCHis) on prenatal valproic acid (VPA)-exposed rats. The VPA was administered to pregnant rats on gestational day 12.5 to induce a model of autism. The offspring were given the treatment of TCHis on postnatal day (PND) 21-50. On PND 43-50, the behavioral analysis of offspring was performed after the treatment of TCHis for 1 h. On PND 50, the offspring were harvested and the brains were collected. The hippocampus and prefrontal cortex were isolated for relevant biochemical detections. The administration of TCHis increased pain sensitivity and improved abnormal social behaviors in prenatal VPA-exposed rats. Prenatal exposure of VPA induced neuronal loss and apoptosis, enhanced reactive oxygen species (ROS) production, and promoted oxidative stress in hippocampus and prefrontal cortex, whereas these effects were reversed by the postnatal treatment of TCHis. In addition, postnatal administration of TCHis ameliorated mitochondrial function in hippocampus and prefrontal cortex of prenatal VPA-exposed rats. This study concluded that postnatal treatment of TCHis reduced oxidative stress and ameliorated abnormal behavior in a prenatal VPA-induced rat model of autism.

Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues.

BACKGROUND: The developmental toxicity potential (dTP) concentration from the devTOX quickPredict (devTOXqP ) assay, a metabolomics-based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOXqP assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues. METHODS: VPA and a series of structural analogues were tested with the devTOXqP assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations. The EADs were compared to the LELs in rat developmental toxicity studies, human clinical doses, and EADs reported using other in vitro assays. To evaluate the impact of different pharmacokinetic (PK) models on IVIVE outcomes, we compared EADs predicted using various open-source and commercially available PK and physiologically based PK (PBPK) models. To evaluate the effect of in vitro kinetics, an equilibrium distribution model was applied to translate dTP concentrations to free medium concentrations before subsequent IVIVE analyses. RESULTS: The EAD estimates for the VPA analogues based on different PK/PBPK models were quantitatively similar to in vivo data from both rats and humans, where available, and the derived rank order of the chemicals was consistent with observed in vivo developmental toxicity. Different models were identified that provided accurate predictions for rat prenatal LELs and conservative estimates of human safe exposure. The impact of in vitro kinetics on EAD estimates is chemical-dependent. EADs from this study were within range of predicted doses from other in vitro and model organism data. CONCLUSIONS: This study highlights the importance of pharmacokinetic considerations when using in vitro assays and demonstrates the utility of the devTOXqP human stem cell-based platform to quantitatively assess a chemical's developmental toxicity potency.

Prenatal GABAB Receptor Agonist Administration Corrects the Inheritance of Autism-Like Core Behaviors in Offspring of Mice Prenatally Exposed to Valproic Acid.

This study was performed to evaluate the effects of prenatal baclofen (a GABAB receptor agonist) treatment on the inheritance of autism-like behaviors in valproic acid (VPA)-exposed mice. VPA model mice (first generation, F1) that were prenatally exposed to VPA exhibited robust core autism-like behaviors, and we found that oral administration of baclofen to F1 mice corrected their autism-like behavioral phenotypes at an early age. Based on a previous epigenetics study, we mated the F1 male offspring with litter females to produce the second generation (F2). The F2 male mice showed obvious inheritance of autism-like phenotypes from F1 mice, implying the heritability of autism symptoms in patients with prenatal VPA exposure. Furthermore, we found prenatal baclofen administration was associated with beneficial effects on the autism-like phenotype in F2 male mice. This may have involved corrections in the density of total/mature dendritic spines in the hippocampus (HC) and medial prefrontal cortex (mPFC), normalizing synaptic plasticity. In this research, GABAB receptor agonist administration corrected the core autism-like behaviors of F1 mice and protected against the inheritance of neurodevelopmental disorders in the offspring of F1 mice, suggesting the potential of early intervention with GABAB receptor agonists in the treatment of neurodevelopmental disorders.

Pearls for the diagnosis and possible pathophysiological mechanisms of valproic acid-induced lupus erythematosus: A literature review.

Background: Drug-induced lupus erythematosus (DILE) accounts for 10-15% of systemic lupus erythematosus (SLE) cases, with more than 100 pharmaceutical agents implicated in its development. Depending on the offending drug, clinical and serological manifestations present great variability and, thus, DILE may be overlooked in clinical practice. Valproic acid (VPA) - induced lupus erythematosus has not been analytically reported in the literature, rendering the recognition of such cases even more difficult.Objective: The aim of this study was to analyze VPA - induced lupus features and to discuss possible pathophysiological mechanisms.Materials and Methods: This literature review was conducted in PubMed and Embase databases in June 2021, in search of DILE cases induced by VPA. We found 164 manuscripts, out of which 140 articles regarding other adverse effects or drugs were discarded. Finally, 15 cases fulfilled the eligibility criteria to be included in this review.Results: Although SLE is more common in females, VPA-induced lupus presented a male predilection. Patients developed DILE within the first three months of treatment with VPA at a percentage of 50%, whereas four patients from one to five years after VPA initiation. DILE frequently presented with mild symptoms. In most patients, serositis manifested with polyarthritis, pleural effusion or pericarditis. Notably, one patient presented with Rowell's syndrome, a rare subtype of lupus erythematosus with erythema multiforme and speckled pattern of antinuclear antibodies (ANAs). Central nervous system, renal and skin involvement was scarcely observed. Cytopenia was noted in 7 patients. Immunological findings included positive ANAs in the vast majority of the patients (86.7%), positive anti-histone antibodies in five, positive anti-dsDNA antibodies in three and hypocomplementemia in two patients. Despite the prompt resolution of clinical symptoms after VPA discontinuation, serological abnormalities persisted up to 18 months. Apart from the discontinuation of VPA administration for the resolution of DILE, treatment included corticosteroids in 8 cases.Conclusion: Valproic acid has been implicated in several cases of DILE. Clinicians should be aware of this entity and recognize it promptly to ensure a favorable outcome. Possible pathophysiologic associations may be extrapolated, but a clearer understanding of this syndrome is to be gained by further studies.

Histone deacetylase inhibitor attenuates intestinal mucosal injury in fatally scalded rats.

Background: Severe burns, trauma and shock can cause intestinal epithelial barrier dysfunction, which can lead to intestinal endotoxemia and even sepsis and multi-organ dysfunction. Many studies have shown that histone deacetylase inhibitors (HDACIs) can improve cell tolerance to hypoxia and inflammation, thus protecting the functions of important organs in the body, and at the same time, inhibiting the degradation of tight junction (TJ) proteins, protecting the intercellular barrier, and reducing tissue edema and organ damage. However, the mechanism is unclear. Methods: Eighty male Sprague-Dawley rats (weighing 280-300 g) with a 50% total body surface area full-thickness dermal burn were randomly assigned to 4 groups (20 rats/group): sham control (SC group), scald + normal saline (SN group), scald + 2-methyl-2pentenoic acid (2M2P group), and scald + valproic acid (VPA group). After scalding, we measured the following parameters at various time intervals postburn injury: intestinal mucosal injury score, diamine oxidase (DAO) activity, intestinal protein expression of acetyl histone H3 at K9 (Ac-H3K9), hypoxia inducible factor 1α (HIF-1α), erythropoietin (EPO), zonula occludens-1 (ZO-1), endothelial nitric oxide synthase (eNOS) content, nitric oxide (NO) content, and intestinal mucosal blood flow (IMBF). Results: Intestinal mucosa showed significant morphologic injury at 4 and 8 hours after scalding that was attenuated by VPA. DAO activity in the VPA group was significantly decreased compared with the other scald groups. At 4 and 8 hours after scalding, VPA enhanced Ac-H3K9 and ZO-1 expression and decreased HIF-1α and EPO expression in the intestine compared with the other scald groups. At 4 and 8 hours after scalding, eNOS and NO protein content and IMBF in the VPA group were markedly increased compared with the other scald groups. Conclusions: HDACIs attenuated intestinal mucosal injury in fatally scalded rats. This may have involved VPA enhancing Ac-H3K9 and ZO-1 expression, inhibiting HIF-1α and EPO expression and inducing eNOS and NO increments.

Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells.

Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1-5 mM), a well-known histone deacetylase (HDAC) inhibitor, strongly inhibited TMSC proliferation without altering MSC-specific surface markers, CD14, 34, 45, 73, 90 and 105. However, CD146 expression increased at 5 mM VPA. VPA increased osteogenic differentiation of TMSCs but decreased adipogenesis and chondrogenesis, as evidenced by the cell-specific staining of differentiation. The former was validated by the increased osteocalcin (OCN). The changes in CCN1 by VPA was biphasic; it increased until 48 h and decreased thereafter. Knockdown of CCN1 by using siRNA inhibited the osteogenic effect of VPA. VPA had no effect on CCN1 mRNA expression, but inhibition of protein synthesis by cycloheximide showed that VPA slowed down the CCN1 protein degradation. Moreover, overexpression of HDAC1 completely inhibited VPA-induced CCN1. Our results indicate that VPA inhibits the HDAC1, inducing CCN1 protein stability rather than gene expression, thereby promoting osteogenic differentiation of TMSCs. These findings present the noble implication of VPA as an inhibitor of HDAC1 to facilitate CCN1-induced osteogenic differentiation of MSCs.

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies.

In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of "epigenetic human diseases".

Long-term use of valproic acid reduced mortality in bipolar disorder patients in a Taiwanese population: An association analysis using the national health insurance research database (NHIRD).

OBJECTIVE: Valproic acid (VPA) is used for the treatment of epilepsy and bipolar disorder (BD). The aims of this study was to examine that long-term VPA use affects mortality in BD patients. METHODS: Association analysis was conducted using the National Health Insurance Research Database (NHIRD) of Taiwan. The long-term VPA use group was selected as patients treated with VPA for BD who used VPA only. The control group consisted of BD patients who were not treated with VPA or lithium. The lithium use group consisted by BD patients used lithium only was also joined the analysis. The cofactors included age (>65 years), sex and the Charlson Comorbidity Index. RESULTS: The hazard ratio (HR) of mortality for the VPA group was 0.83 (95% confidence interval (CI), (0.70-0.99); P = 0.04) and the result of lithium group did not reach statistical significance. Furthermore only the duration> 3 years subgroup had a significantly lower incidence of mortality than the control group, with an HR of 0.54 (95% CI, (0.42-0.70); P < 0.001) and 0.58 (95% CI, (0.38, 0.89); P = 0.013 in VPA and lithium groups, respectively. The effect of VPA treatment in terms of reducing the risk of mortality was evidenced only in the male population and the <65 years subgroup (HR: 0.75; 95% CI, (0.59-0.95), and 0.78; 95% CI, (0.64-0.96), respectively). The major limitation of this study was that the causes of death of the expired subjects were not available. CONCLUSION: Long-term VPA use decreases the risk of mortality in BD patients, especially in the male population and those aged <65 years.

Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model.

Prenatal exposure to valproic acid (VPA) has been implicated in the manifestation of autism spectrum disorder (ASD)-like behavioral and functional changes both in human and rodents including mice and rats. The objective of this study was to determine metabolomics profiling and biomarkers related to VPA-induced symptoms resembling ASD using proton nuclear magnetic resonance (1H-NMR) spectral data. VPA was administered to pregnant rats at gestation day 12.5 and effects measured subsequently in male 4-week-old offspring pups. The sociability of VPA-treated animals was significantly diminished and exhibited ASD-like behavior as evidenced by reduction of social adaptation disorder and lack of social interactions. To find biomarkers related to ASD, the following were collected prefrontal brain cortices, urine bladder and blood samples directly from heart puncture. In all samples, principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) displayed significant clustering pattern differences between control and treated groups. Valine, taurine, myo-inositol, 3-hydroxybutyrate and 1,3-dihydroxyacetone were significantly decreased in brain cortices in treated rats. Serum metabolites of glucose, creatine phosphate, lactate, glutamine and threonine were significantly increased in VPA-administered animals. Urinary metabolites of pimelate, 3-hydroxyisovalerate and valerate were significantly reduced in VPA-treated rat, whereas galactose and galactonate levels were elevated. Various metabolites were associated with mitochondrial dysfunction metabolism and central nervous system disorders. Data demonstrated that VPA-induced alterations in endogenous metabolites of serum, urine, and brain cortex which might prove useful as biomarkers for symptoms resembling ASD as a model of this disorder.

Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment.

Glioma, characterized by infiltrative growth and treatment resistance, is regarded as the most prevalent intracranial malignant tumor. Due to its poor prognosis, accumulating investigation has been performed for improvement of overall survival (OS) and progression-free survival (PFS) in glioma patients. Valproic acid (VPA), one of the most common histone deacetylase inhibitors (HDACIs), has been detected to directly or synergistically exert inhibitory effects on glioma in vitro and in vivo. In this review, we generalize the latest advances of VPA in treating glioma and its underlying mechanisms and clinical implications, providing a clearer profile for clinical application of VPA as a therapeutic agent for glioma.

Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (p < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.

Valproic Acid and Breast Cancer: State of the Art in 2021.

Valproic acid (2-propylpentanoic acid, VPA) is a short-chain fatty acid, a member of the group of histone deacetylase inhibitors (HDIs). VPA has been successfully used in the treatment of epilepsy, bipolar disorders, and schizophrenia for over 50 years. Numerous in vitro and in vivo pre-clinical studies suggest that this well-known anticonvulsant drug significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. Breast cancer (BC) is the most common malignancy affecting women worldwide. Despite significant progress in the treatment of BC, serious adverse effects, high toxicity to normal cells, and the occurrence of multi-drug resistance (MDR) still limit the effective therapy of BC patients. Thus, new agents which improve the effectiveness of currently used methods, decrease the emergence of MDR, and increase disease-free survival are highly needed. This review focuses on in vitro and in vivo experimental data on VPA, applied individually or in combination with other anti-cancer agents, in the treatment of different histological subtypes of BC.