Valproate Research Articles

Rapid effects of valproic acid on the fetal brain transcriptome: implications for brain development and autism

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 258 genes that have been reported to modulate fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. Notably, at least 40 genes that are known to regulate embryonic neurogenesis were dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or downregulated by VPA in the fetal brain and (b) associated with autism and/or known to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The genes meeting these criteria provide potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.

Mechanistic insights into retinoic-acid treatment for autism in the improvement of social behavior: evidence from a multi omics study in rats

BackgroundAutism spectrum disorder (ASD) is a lifelong condition. It is characterized by complex etiologies, including disruptions in exogenous retinoic acid (RA) signaling, which may serve as an environmental risk factor. Targeting the RA pathway presents a promising therapeutic avenue, though the precise mechanisms remain to be elucidated. MethodsFemale Sprague–Dawley rats were treated with valproic acid (VPA) during pregnancy to induce an ASD model in their offspring. Some offspring received RA treatment postnatally. Social behavior and brain-functional connectivity were assessed using behavioral tests and functional magnetic resonance imaging (fMRI), respectively. Transcriptomics analysis and proteomics analysis of the hypothalamus identified differentially expressed genes (DEGs) and differentially expressed proteins (DEPs). These were intersected with ASD pathogenic genes (APGs) and ASD pathogenic proteins (APPs) to identify differentially expressed APGs (DE-APGs) and differentially expressed APPs (DE-APPs), which were validated by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Analyses of enrichment of signaling pathways were done using the Kyoto Encyclopedia of Genes and Genomes database. ResultsRA treatment significantly improved social behaviors and revealed distinct patterns of hypo- and hyper-connectivity across various brain regions, with notable changes involving the hypothalamus and facial nerve. Differential analysis revealed 4165 DEGs (DEG 1) and 329 DEPs (DEP 1) between control and VPA groups, and 1610 DEGs (DEG 2) and 197 DEPs (DEP 2) between VPA and RA supplementation (RAS) groups. Twenty-two DE-APGs and five DE-APPs were identified, with key associations found between proteins such as Tbl1xr1 and Myo5a and >13 genes including Nrxn1, Cacna1e, and Gabrb2. Significant alterations in DE-APGs, including Grin2b, Nrxn1, Cacna1e, and Gabrb2, were confirmed via real-time RT-PCR and western blotting. In addition, 22 key signaling pathways were enriched in DEPs and DEGs. ConclusionRA supplementation in ASD rats induced by VPA may ameliorate social deficits and modulated functional connectivity, especially in the hypothalamus and facial nerve regions. This suggests potential therapeutic benefits for neural circuitry dysregulation in ASD. Additionally, RA altered critical gene and protein expressions in hypothalamus, implicating its role in modulating key signaling pathways to mitigate social deficits in ASD. This study provides new insights into the molecular mechanisms of ASD and supports the development of novel therapeutic strategies.

Genetic machinery which accompanies metaplasticity operates differentially in experimental model of autism

AbstractThe present study investigated metaplasticity‐related mRNA expressions in valproic acid (VPA)‐rats, focusing on the PI3K/AKT pathway. Wistar dams were treated with a single intraperitoneal injection of 600 mg/kg VPA or saline on embryonic day E12.5 or an equal volume of saline solution. Three behavioral tests were conducted on these males' offspring: grid‐walking test, negative geotaxis test, and three‐chamber social interaction test. Metaplasticity was induced in 60‐day‐old male progeny by giving high‐frequency stimulation for 5 minutes following low‐frequency stimulation to the perforant pathway. For the baseline stimulation protocol (n = 6), stimulation was delivered to the dentate gyrus at the previously determined stimulation intensity (0.33 Hz 0.175 msec 30 s) for 75 min. The percent change of slope of field excitatory postsynaptic potential (fEPSP) and amplitude of population spike were calculated 55–60 min after induction protocol. The mRNA levels of PI3K, PTEN, AKT, GSK‐3β, and MAPT were measured in the hippocampus by using quantitative rt‐PCR. We found that offspring of VPA‐treated rats showed significantly impaired sensorimotor coordination, decreased sociability, impaired preference for social novelty, and reduced input–output curve of fEPSP slope, compared to control animals. Despite a similar metaplastic response, mRNA levels of genes of interest were similar but considerably down‐regulated after induction in offspring of VPA‐treated dams. Our study provides evidence that the induced expression of autism‐related genes has evolved to enable an adaptation mechanism during metaplastic control of long‐term potentiation.

Taprenepag restores maternal–fetal interface homeostasis for the treatment of neurodevelopmental disorders

Background and purposeNeurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development.Experimental ApproachThe maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons.Key resultsIn VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE2/PTGER-2/IDO-1 and abolished these alterations.ConclusionTaprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development.

Ameliorative effects of Edaravone against Valproic Acid-Induced kidney damage.

Valproic acid (VPA) is a well-known and increasingly documented antiepileptic drug that has been widely used in the treatment of epilepsy and/or epilepsy-related disorders. Prolonged clinical use of VPA has been reported to cause side effects such as nephrotoxicity. Edaravone (EDA) is a powerful free radical scavenger. The aim of the study was to investigate the protective effects of EDA against VPA-induced oxidative renal injury. Four experimental groups were formed by randomly assigning thirty-eight male Sprague Dawley rats. The first group, (Control Group, n = 8), consisted of healthy rats. The second group, (Group II, n = 10), comprised control rats given intraperitoneally EDA (30mg/kg/day) for seven days. The third group (Group III, n = 10) was administered intraperitoneally only VPA (500mg/kg/day) for seven days. The last group (Group IV, n = 10) was treated with VPA + EDA for seven days. On the 8th day, kidney tissues were immediately removed from rats. In kidney homogenates, reduced glutathione levels and Na/K+-ATPase, paraoxonase1 and prolidase activities were remarkably decreased while catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, myeloperoxidase, and xanthine oxidase activities and lipid peroxidation, protein carbonyl, advanced oxidized protein products, and hydroxyproline contents were notably elevated in VPA given group. Consistently, administration of EDA decreased renal degenerative changes seen in the kidney tissue of VPA given rats. Treatment with EDA in the VPA group significantly resulted in the recovery of both biochemical and histopathological alterations. As a result, EDA is potentially beneficial to revert oxidative renal damage induced by VPA.

Pediatric Bipolar Disorder: Challenges in Diagnosis and Treatment.

Despite an opportunity to prevent adult psychopathology associated with bipolar disorder through early diagnosis in children, there is insufficient information and awareness among healthcare providers about the unique features and treatment of mania and its comorbid conditions in children. Converging evidence from disparate sites describe a developmentally distinct presentation of bipolar disorder in youth that is highly morbid, persistent and responds to treatment with the mood stabilizer medications used in the treatment of adult bipolar disorder, such as divalproex sodium and carbamazepine. Some are additionally approved for use in pediatric populations including, for manic or mixed states, risperidone, aripiprazole, and asenapine for those aged 10-17years and also including lithium and olanzapine for ages 13-17years. Quetiapine is approved as monotherapy or as adjunct to lithium or divalproex sodium for manic states in those aged 10-17years. Delayed or missed diagnosis, inappropriate treatment, worsening course, and treatment resistance unfortunately still occur. While an array of mood-stabilizing medications is available for treatment, such as second-generation antipsychotics, lithium, and anticonvulsants, these can be only partially effective and fraught with annoying and serious side effects. This article will review current practice in the diagnosis and treatment of pediatric bipolar disorder and its comorbid conditions, highlighting areas of need for future research.

Retraction: Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

Retraction: Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

Induction of neuronal differentiation in glioma cells by histone deacetylase inhibitors based on Connectivity Map discovery.

Neuron conversion leads to proliferation inhibition of glioma cells and may be an effective strategy to combat glioma and prevent recurrence. In this study, drug repositioning based on Connectivity Map (CMap) was conducted to discover drugs that could induce the differentiation of glioma cells into neuron-like cells, complemented by in vitro experimental validation. Downregulated neuronal genes in glioma were identified by the Human Protein Atlas database and the GeneCards database, and enrichment analysis and Gene Expression Profiling Interactive Analysis (GEPIA) were performed to ensure their reliability before they were uploaded to CMap for drug screening. The potential drug targets were screened through GEPIA and validated by the Chinese Glioma Genome Atlas database. Cell morphology, proliferation, and neuronal marker expression were detected to evaluate the differentiation-inducing effect of the selected drugs. The bioinformatics analysis identified histone deacetylase (HDAC) inhibitors as potential drugs. HDAC1/3/7 showed the relationship with neuronal genes, and HDAC1 showed the highest level of inverse correlation with neuronal gene expression and had the highest hazard ratio. In vitro study showed that both the pan-HDAC inhibitor belinostat, class I and class IIa HDAC inhibitor valproic acid, and selective HDAC1 inhibitor parthenolide induce morphology alteration, proliferation inhibition, expression of neuronal markers including microtubule-associated protein 2, neuronal nuclei antigen, and synaptophysin in U87 cells. This study suggests that the HDAC inhibitors belinostat, valproic acid, and parthenolide can induce glioma cells to differentiate into neuron-like cells, with HDAC1/3/7 being the likely drug targets and HDAC1 potentially playing an important role in this.

Study on the therapeutic potential of induced neural stem cells for Alzheimer's disease in mice

Induced neural stem cells (iNSCs), which have similar properties to neural stem cells and are able to self-proliferate and differentiate into neural cell lineages, are expected to be potential cells for the treatment of neurodegeneration disease. However, cell therapy based on iNSCs transplantation is limited by the inability to acquire sufficient quantities of iNSCs. Previous studies have found that mouse and human fibroblasts can be directly reprogrammed into iNSCs with a single factor, Sox2. Here, we induced mouse embryonic fibroblasts (MEFs) into iNSCs by combining valproic acid (VPA) with the induction factor Sox2, and the results showed that VPA significantly improved the conversion efficiency of fibroblasts to iNSCs. The iNSCs exhibited typical neurosphere-like structures that can express NSCs markers, such as Sox2, Nestin, Sox1, and Zbtb16, and could differentiate into neurons, astrocytes, and oligodendrocytes in vitro. Subsequently, the iNSCs were stereotactically transplanted into the hippocampus of APP/PS1 double transgenic mice (AD mice). Post-transplantation, the iNSCs showed long-term survival, migrated over long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Importantly, the cognitive abilities of APP/PS1 mice transplanted with iNSCs exhibited significant functional recovery. These findings suggest that VPA enhances the conversion efficiency of fibroblasts into iNSCs when used in combination with Sox2, and iNSCs hold promise as a potential donor material for transplantation therapy in Alzheimer’s disease.

PBPK modelling for the evaluation of drug-drug interaction between meropenem and valproic acid.

The present study aimed to quantitatively investigate the potential drug-drug interaction (DDI) mechanism between meropenem (MEPM) and valproic acid (VPA). In the present study, we firstly developed a physiologically based pharmacokinetic (PBPK) model of MEPM and VPA. The verified PBPK model was then used to quantitatively investigate the potential DDI between MEPM and VPA. The effect of genetic polymorphisms of acylpeptide hydrolase (APEH) on DDI was also evaluated. In our simulation, the plasma concentration of hydrolysate of VPAG decreased to 63% when combined with MEPM. Total plasma concentration of VPA before carbapenem use was 53.61 mg/L, whereas it was 45.42 mg/L during carbapenem use. The inhibition of hydrolysis of VPAG by MEPM alone could not result in a rapid and substantial decrease in the plasma concentration of VPA. Parameter sensitivity analysis showed that the changes of absorption played an important role in the maximum plasma concentration (Cmax) of VPA, whereas area under the plasma concentration-time profile (AUC) was more susceptible to elimination changes. In addition, a decrease in APEH activity had little impact on the plasma pharmacokinetics of VPA. The DDI between MEPM and VPA might be a comprehensive result of multiple factors. On the basis of our simulation, interval medication of MEPM injection and VPA immediate release tablet at 4-6h timed interval was recommended, or intravenous administration of VPA solution was preferred when combination regimen was necessary in a clinical setting.

The effects of hesperidin on valproic acid-induced reduction in hippocampal neurogenesis through the antioxidant and apoptotic pathways in adult rats

Treatment with valproic acid (VPA) can induce oxidative stress, leading to neuronal degeneration. Hesperidin (HSD) has an antioxidant function that can mitigate oxidative stress, thereby promoting hippocampal neurogenesis. Because brain function and memory are reliant on hippocampal neurogenesis, this work is planned to elucidate the effects of HSD on the VPA-induced alterations in hippocampal neurogenesis and apoptosis via oxidative damage. Twenty-four male Sprague-Dawley rats were grouped into the vehicle, VPA, HSD, and VPA + HSD groups. After administration, the hippocampi and prefrontal cortex were harvested for p21 staining, assessment of MDA, CAT, SOD, and GPx, and Western blotting analysis of Nrf2, Bax, caspase3, and Bcl-2 proteins. The results exhibited a significantly elevated level of p21-positive cells in VPA-treated rats, indicating cell cycle arrest in hippocampal neurogenesis. Additionally, our findings demonstrated a notable rise in oxidative stress, a decrease in antioxidant enzyme activity and the transcription factor Nrf2 in VPA-treated rats. Furthermore, VPA induced apoptotic activities, as substantiated by the upregulation of Bax and caspase3, and the downregulation of Bcl-2. These findings demonstrate that HSD can reduce oxidative stress levels, thereby mitigating the arrest of the cell cycle and apoptotic activity induced by VPA treatment in both the hippocampus and prefrontal cortex.

Striatal interneuron imbalance in a valproic acid-induced model of autism in rodents is accompanied by atypical somatosensory processing.

Autism spectrum disorder (ASD) is characterized by deficits in social interaction and communication, cognitive rigidity, and atypical sensory processing. Recent studies suggest that the basal ganglia, specifically the striatum (NSt), plays an important role in ASD. While striatal interneurons, including cholinergic (ChAT+) and parvalbumin-positive (PV+) GABAergic neurons, have been described to be altered in animal models of ASD, their specific contribution remains elusive. Here, we combined behavioral, anatomical, and electrophysiological quantifications to explore if interneuron balance could be implicated in atypical sensory processing in cortical and striatal somatosensory regions of rats subjected to a valproic acid (VPA) model of ASD. We found that VPA animals showed a significant decrease in the number of ChAT+ and PV+ cells in multiple regions (including the sensorimotor region) of the NSt. We also observed significantly different sensory-evoked responses at the single-neuron and population levels in both striatal and cortical regions, as well as cortico-striatal interactions. Therefore, selective elimination of striatal PV+ neurons only partially recapitulated the effects of VPA, indicating that the mechanisms behind the VPA phenotype are much more complex than the elimination of a particular neural subpopulation. Our results indicate that VPA exposure induced significant histological changes in ChAT+ and PV+ cells accompanied by atypical sensory-evoked cortico-striatal population dynamics that could partially explain the sensory processing differences associated with ASD.Significance Statement One of the main characteristics of patients with autism spectrum disorder (ASD) is the hypo- or hyper-responses to sensory stimuli. Various studies indicate that a possible explanation for these atypical responses is an imbalance in excitation-inhibition modulated by different types of interneurons. In the present work, we provide evidence that a striatal imbalance in ChAT+ and PV+ levels could partly explain behavioral and somatosensory processing differences associated with the valproic acid-induced ASD model.

Formulation and Evaluation of Valproic Acid Microemulsions for Enhanced Transfollicular Delivery in Guinea Pig Skin.

Valproic acid (VPA) is used to treat various neurological and psychiatric conditions. While oral VPA can cause hair loss, topical application has shown potential for hair regeneration. This study aimed to develop and evaluate microemulsion (ME) formulations of VPA for enhanced transfollicular delivery. VPA-loaded MEs were prepared using oleic acid, Transcutol P, Tween 80, Labrasol, and Capryol 90. The MEs were characterized for physicochemical properties, stability, invitro release, and exvivo permeation through the hairy abdominal and nonhairy ear skin of guinea pigs. Eight stable ME formulations were developed with droplet sizes ranging from 10 to 24 nm, pH 4.6 to 5.2, and viscosity 77 to 85 cps. Invitro release studies showed controlled release profiles over 24 h. Permeation studies revealed enhanced drug delivery through both follicular and nonfollicular pathways compared with aqueous VPA solution. Formulations with higher surfactant/cosurfactant ratios showed increased permeation through the follicular pathway. The ME formulations significantly enhanced VPA penetration into both epidermal and follicular pathways compared with aqueous solution. The composition of the MEs, particularly the oil content, water content, and surfactant/cosurfactant ratio, played a crucial role in determining the physicochemical properties and skin permeation parameters of VPA.

Effect of UGT1A6 and UGT2B7 polymorphisms on the valproic acid serum concentration and drug-induced liver injury.

Aim: Valproic acid (VPA) is a classic broad-spectrum antiepileptic drug, with significant pharmacokinetic variability. Genetic polymorphisms contribute to this variability, influencing both VPA trough serum concentration (VPA concentration) and VPA-induced liver injury. Our study aims to investigate the association between polymorphisms of uridine diphosphate glucuronyl transferase (UGT) 1A6, UGT2B7 and VPA concentration and screen for potential genetic loci affecting VPA-induced liver injury.Methods: This study included epilepsy patients treated with VPA. PCR-RFLP method was used to determine the genotypes of UGT1A6 and UGT2B7. Chemiluminescent microparticle immunoassay was used to measure VPA concentration. Multiple linear regression and logistic regression were employed to analyze factors influencing VPA concentration and VPA-induced liver injury, respectively.Results: The correlation between UGT polymorphism and VPA concentration was analyzed in 133 samples. For VPA-induced liver injury, 105 patients were analyzed, with 29 in the liver injury group and 76 in the control group. Our finding showed patients with the UGT1A6-T19G variant had significantly lower VPA concentrations compared with wild-type patients and UGT1A6-T19G, A541G, A552C and UGT2B7-C802T, G211T, A268G polymorphisms showed no impact on VPA-induced liver injury.Conclusion: This study demonstrated UGT1A6-T19G polymorphisms affected the VPA concentration, providing a theoretical basis for the individualized clinical use of VPA.

Integrated proteomics and metabolomics analyses reveal new insights into the antitumor effects of valproic acid plus simvastatin combination in a prostate cancer xenograft model associated with downmodulation of YAP/TAZ signaling

BackgroundDespite advancements in therapeutic approaches, including taxane-based chemotherapy and androgen receptor-targeting agents, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable tumor, highlighting the need for novel strategies that can target the complexities of this disease and bypass the development of drug resistance mechanisms. We previously demonstrated the synergistic antitumor interaction of valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitory activity, with the lipid-lowering drug simvastatin (SIM). This combination sensitizes mCRPC cells to docetaxel treatment both in vitro and in vivo by targeting the cancer stem cell compartment via mevalonate pathway/YAP axis modulation.MethodsHere, using a combined proteomic and metabolomic/lipidomic approach, we characterized tumor samples derived from 22Rv1 mCRPC cell-xenografted mice treated with or without VPA/SIM and performed an in-depth bioinformatics analysis.ResultsWe confirmed the specific impact of VPA/SIM on the Hippo–YAP signaling pathway, which is functionally related to the modulation of cancer-related extracellular matrix biology and metabolic reprogramming, providing further insights into the molecular mechanism of the antitumor effects of VPA/SIM.ConclusionsIn this study, we present an in-depth exploration of the potential to repurpose two generic, safe drugs for mCRPC treatment, valproic acid (VPA) and simvastatin (SIM), which already show antitumor efficacy in combination, primarily affecting the cancer stem cell compartment via MVP/YAP axis modulation. Bioinformatics analysis of the LC‒MS/MS and 1H‒NMR metabolomics/lipidomics results confirmed the specific impact of VPA/SIM on Hippo–YAP.

Design of optimal concentrations for in vitro cytotoxicity experiments.

Concentration-dependent cytotoxicity experiments are frequently used in toxicology. Although it has been reported that an adequate choice of concentrations improves the quality of the statistical inference substantially, a recent literature review of three major toxicological journals has shown that the corresponding methods are rarely used in toxicological practice. In this study the performance of different sets of concentrations, also called designs, are analyzed, while the overall goal is to promote the advantages of optimal design procedures and to present a user-friendly guideline for planning new cytotoxicity concentration-response experiments. We compare the frequently used log-equidistant design to a Bayesian design, which is constructed by methods of optimum design theory. Using both a dense data set of concentration-cytotoxicity data of valproic acid (VPA) and regular assay data of 104 substances, the performance of the different designs is analyzed in two scenarios, where detailed previous knowledge on VPA is available or not. The results show that it is critical to apply a specific design strategy to determine optimal concentrations for cytotoxicity testing. In particular, the Bayesian design technique with and without incorporating pre-existing knowledge of a specific test substance resulted in a more precise statistical inference than the other used designs. Finally, we present a guideline for upcoming experiments and an accessible user-friendly Shiny app (see http://shiny.statistik.tu-dortmund.de:8080/app/occe ).

Characteristics of patients with drug-resistant epilepsy in a tertiary hospital

Drug-resistant epilepsy has a cumulative incidence between 14 and 20% of patients with epilepsy. It is associated with more comorbidities and with higher healthcare expenditure and impact on quality of life. A retrospective longitudinal descriptive study was performed covering the period from 01/01/2010 to 02/28/2024. All patients with epilepsy seen in the Pediatric Neurology unit of our center were collected and a review of medical records was carried out to collect the characteristics and evolution during the study period. The classification and definitions used were those established by the International League Against Epilepsy. A total of 325 patients with epilepsy were identified, with a cumulative incidence of DRE of 29%. The most frequent etiology was structural both in all patients with epilepsy (22%), and in drug-resistant epilepsy (36%). A statistically significant association was established between refractoriness and genetic and structural causes, and between having status epilepticus and the development of drug-resistant epilepsy. Seventy-nine percent of patients with drug-resistant epilepsy developed epileptic encephalopathy. The most commonly used antiseizure drug was valproic acid (90%), 19% received a ketogenic diet and 4.2% received epilepsy surgery. In our setting the incidence of drug-resistant epilepsy is high, more so than previously described. Genetic and structural etiologies are associated with a higher incidence. Having suffered status epilepticus is associated with refractoriness. A higher incidence was observed in patients with defined electroclinical syndromes, probably influenced by epileptic and developmental encephalopathies.

Valproate Administration to Adult 5xFAD Mice Upregulates Expression of Neprilysin and Improves Olfaction and Memory.

It is well known that the development of neurodegeneration, and especially Alzheimer's disease (AD), is often accompanied by impaired olfaction which precedes memory loss. A neuropeptidase neprilysin (NEP)-a principal amyloid-degrading enzyme in the brain-was also shown to be involved in olfactory signalling. Previously we have demonstrated that 5xFAD mice develop olfactory deficit by the age of 6months which correlated with reduced NEP expression in the brain areas involved in olfactory signalling. The aim of this study was to analyse the effect of administration of a histone deacetylase inhibitor, valproic acid (VA), to adult 5xFAD mice on their olfaction and memory as well as on brain morphology and NEP expression in the parietal cortex (PC) and hippocampus (Hip). The data obtained demonstrated that administration of VA to 7-month-old mice (200mg/kg of body weight) for 28days resulted in improvement of their memory in the Morris water maze as well as olfaction in the odor preference and food search tests. This correlated with increased expression of NEP in the PC and Hip as well as a reduced number of amyloid plaques in these brain areas. This strongly suggests that NEP can be considered an important therapeutic target not only in AD but also in olfactory loss.

The Influence of the Hydroalcoholic Extract of Polypodium vulgare L. on Pentylenetetrazole-induced Seizures and Its Comparison with the Impact of Sodium Valproate in a Rat Model

The Influence of the Hydroalcoholic Extract of Polypodium vulgare L. on Pentylenetetrazole-induced Seizures and Its Comparison with the Impact of Sodium Valproate in a Rat Model

Epileptic encephalopathy, autism and cognitive deficit caused by the SYNGAP1 gene mutation

The paper analyzes data from scientific publications and presents a clinical case study of a rare genetic epileptic encephalopathy caused by a mutation in the SYNGAP1 gene. The case study focuses on a 4-year-old girl who has been diagnosed with epileptic encephalopathy due to the mutation. The paper describes the anamnesis of the child’s illness, including family history, neurological, neuropsychological, and speech assessments, as well as the results of genetic testing, electroencephalography, and magnetic resonance imaging (MRI). The findings indicate that the main symptoms of the condition are typically epilepsy, autism spectrum disorder, difficulty with phrasal speech, and mental retardation. Common types of seizures include atypical absence seizures, myoclonic seizures, atonic seizures, and eyelid myoclonia with absences. On the electroencephalogram, there is a slowdown in occipital activity and diffuse, prolonged «peak-polypic-slow-wave» complexes. Pathognomonic neuroimaging changes in the brain are typically absent. Valproic acid, levetiracetam, and ethosuximide have been shown to be the most effective treatments for controlling epileptic seizures. Due to the rarity of this syndrome, the authors have provided a detailed clinical case report from their practice.Conclusion. SYNGAP1-related epileptic encephalopathy has a specific clinical presentation, including characteristic EEG findings and a particular pattern of seizures. The diagnostic approach for children with this condition, autism spectrum disorder, and delayed language development should include video electroencephalography with sleep deprivation, as well as genetic testing if necessary, using next-generation sequencing, to ensure early detection and appropriate treatment planning.