Valproic Acid Treatment Research Articles

The impact of valproic acid treatment on weight gain in pediatric patients with epilepsy.

Valproic acid (VPA) is an antiepileptic drug, used for focal and generalized seizure. VPA treatment resulted in significant weight gain but there are no systematic data about the prevalence of this side effect. The aim of the study was to evaluate the weight gain of a pediatric population with epilepsy. We enrolled 38 patients, 17 females and 21 males with a mean age of 8.2±4.4 years. We evaluated data about height, weight and BMI at beginning of treatment and at 24, 36 and 48 months of follow-up. There is a statistically significant difference between the percentile value of weight and BMI at baseline and at 36 and 48 months of follow-up (P<0.01) but there is not statistically significant difference between the percentile value of height (P=0.22 and P=0.18). We believe that a nutritional support should be guaranteed to the pediatric patients with epilepsy that begin the VPA therapy.

4-Phenylbutyric Acid Plus Valproic Acid Exhibits the Therapeutic and Neuroprotective Effects in Acute Seizures Induced by Pentylenetetrazole.

Endoplasmic reticulum (ER) stress and apoptosis are implicated in the pathogenesis of epilepsy. Here we examine the effects of valproic acid (VA) plus 4-phenylbutyric acid (4-PBA) on abnormal electrical brain activity, ER stress and apoptosis in acute seizures induced by pentylenetetrazole (PTZ). Forty male rats were randomly divided into five groups, each consisting of 8 rats as follows: Sham, PTZ, VA+PTZ, 4-PBA+PTZ, and VA plus 4-PBA+PTZ. The treated groups received VA, 4-PBA and VA plus 4-PBA by intraperitoneal application for 7days prior to PTZ-induced seizure. On the 8th day, acute epileptic seizures were induced by PTZ (50mg/kg, i.p.) injection, except for the sham group. Then, the seizure stage was observed and ECoG activities were recorded during the 30min. At 24th post seizures, the hippocampus and blood samples were collected for biochemical and histopathological examinations. Administration of VA plus 4-PBA prior to PTZ-induced seizures significantly decreased seizure stage, the duration of generalized tonic-clonic seizure and the total number of spikes as increased the latency to the first myoclonic jerk when compared to the PTZ group. 4-PBA suppressed the increased levels of ER stress markers GRP78 and CHOP in the hippocampus. VA plus 4-PBA treatment before seizures significantly inhibited PTZ-induced elevations of apoptosis-related indicators caspase-3 and caspase-12, and significantly reduced the number of histopathological lesions of the hippocampus region at 24th post seizures. These findings suggest that administration of VA plus 4-PBA prior to PTZ-induced seizures may be involved in the neuroprotective potential of these agents for seizures.

Anti-proliferative and Apoptotic Effects of Valproic Acid on HeLa Cells

Background: Valproic acid (VPA), a branched short-chain fatty acid and histone deacetylase (HDAC) inhibitor, has diverse biological activities in human cells, including anti-cancer properties. Objectives: In the present study, we tested the cytotoxicity of VPA on the proliferation, cell cycle, and apoptosis of the human cervical cancer cell line, HeLa. Methods: HeLa cell line was cultured in Dulbecco’s modified eagle medium (DMEM) and the cytotoxicity effect of VPA (at 0 - 100 mM) on the HeLa cell was evaluated, using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay for 3 incubation times (24, 48, and 72 h). The effects of VPA on cell cycle arrest and apoptosis were evaluated, using flow cytometry. In addition, the alterations in the expression of Bax, Bcl-2, p53, and p21 were assessed with real‐time polymerase chain reaction (PCR). Results: Valproic acid reduced the viability of HeLa cells in a concentration- and time-dependent manner, and the IC50 values at 24, 48, and 72 h were 32.06, 21.29, and 14.51 mM, respectively. Further, VPA treatment remarkably increased the apoptosis of HeLa cells and arrested cells at the sub-G1 phase with a significant reduction in G2-M phase populations. The real-time PCR results demonstrated a significant increase in the expression of pro-apoptotic genes, including Bax, p53, and p21, as well as a reduction in the levels of the anti-apoptotic gene, Bcl-2. Conclusions: Valproic acid inhibits the proliferation of the HeLa cell line through the induction of the intrinsic pathway of apoptosis in a p35-dependent manner.

Effect of Valproic Acid on NLR Family Pyrin Domain Containing 1/3 (NLRP1/3) Inflammasome in Rats with Acute Spinal Cord Injury

Our study assesses valproic acid’s effect on NLRP1/3 inflammasome in rats with acute spinal cord injury (SCI). SD rats were clamped by aneurysm clips to establish SCI model followed by analysis of functional recovery by BBB score, degree of inflammatory infiltration, by H&amp;E staining, NLRP1/NLRP3 and P2X7 level by western blot, IL-1β and IL-18 level by ELISA, blood spinal cord barrier by EVANS blue method. After SCI, the lower limb motor function of rats decreased and recovered after valproic acid treatment (P &lt; 0.05). Inflammatory cell infiltration of SCI group increased and decreased after treatment. After SCI, NLRP1/3 level increased and P2X7 protein level elevated which were reversed after valproic acid treatment (P &lt; 0.05). In rats with SCI, IL-1β level in spinal cord was higher than sham operation and lower after treatment (P &lt; 0.05) without difference of IL-18 between injury group and treatment group (P &gt; 0.05). In addition, fluorescence was higher in injury group than sham operation group and lower in valproic acid injection group than injury group. In conclusion, Valproic acid can promote motor function recovery in rats after SCI and inhibit inflammasome 1 and 3 expression, thereby inhibiting the maturation and release of IL-1β, and reducing P2X7 level after SCI.

ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration.

BackgroundThe ARHGEF9 gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype–phenotype relationship is still unpredictable.MethodsClinical data of the patients and their family members were gathered in a retrospective study. The exome sequencing that was performed on peripheral blood samples was applied for genetic analysis. We used the ARHGEF9 gene as a key word to search the PubMed database for cases of ARHGEF9 gene variants that have previously been reported and summarized the reported ARHGEF9 gene variant sites, their corresponding clinical phenotypes, and effective treatment.ResultsWe described five patients with developmental and epileptic encephalopathy caused by ARHGEF9 gene variants. Among them, the antiepileptic treatment of valproic acid and levetiracetam was effective in two cases individually. The exome sequencing results showed five children with point mutations in the ARHGEF9 gene: p.R365H, p.M388V, p.D213E, and p.R63H. So far, a total of 40 children with ARHGEF9 gene variants have been reported. Their main clinical phenotypes include developmental delay, epilepsy, epileptic encephalopathy, and autism spectrum disorders. The variants reported in the literature, including 22 de novo variants, nine maternal variants, and one unknown variant. There were 20 variants associated with epileptic phenotypes, of which six variants are effective for valproic acid treatment.ConclusionThe genotypes and phenotypes of ARHGEF9 gene variants represent a wide spectrum, and the clinical phenotype of epilepsy is often refractory and the prognosis is poor. The p.R365H, p.M388V, p.D213E, and p.R63H variants have not been reported in the current literature, and our study has expanded the genotype spectrum of ARHGEF9 gene. Our findings indicate that levetiracetam and valproic acid can effectively control seizures in children with epileptic phenotype caused by ARGHEF9 gene variations. These findings will help clinicians improve the level of diagnosis and treatment of the genetic disease.

Valproic acid modulates collagen architecture in the postoperative conjunctival scar.

Valproic acid (VPA), widely used for the treatment of neurological disorders, has anti-fibrotic activity by reducing collagen production in the postoperative conjunctiva. In this study, we investigated the capacity of VPA to modulate the postoperative collagen architecture. Histochemical examination revealed that VPA treatment was associated with the formation of thinner collagen fibers in the postoperative days 7 and 14 scars. At the micrometer scale, measurements by quantitative multiphoton microscopy indicated that VPA reduced mean collagen fiber thickness by 1.25-fold. At the nanometer scale, collagen fibril thickness and diameter measured by transmission electron microscopy were decreased by 1.08- and 1.20-fold, respectively. Moreover, delicate filamentous structures in random aggregates or closely associated with collagen fibrils were frequently observed in VPA-treated tissue. At the molecular level, VPA reduced Col1a1 but induced Matn2, Matn3, and Matn4 in the postoperative day 7 conjunctival tissue. Elevation of matrilin protein expression induced by VPA was sustained till at least postoperative day 14. In primary conjunctival fibroblasts, Matn2 expression was resistant to both VPA and TGF-β2, Matn3 was sensitive to both VPA and TGF-β2 individually and synergistically, while Matn4 was modulable by VPA but not TGF-β2. MATN2, MATN3, and MATN4 localized in close association with COL1A1 in the postoperative conjunctiva. These data indicate that VPA has the capacity to reduce collagen fiber thickness and potentially collagen assembly, in association with matrilin upregulation. These properties suggest potential VPA application for the prevention of fibrotic progression in the postoperative conjunctiva. KEY MESSAGES: VPA reduces collagen fiber and fibril thickness in the postoperative scar. VPA disrupts collagen fiber assembly in conjunctival wound healing. VPA induces MATN2, MATN3, and MATN4 in the postoperative scar.

Valproic acid regulates sodium‐dependent vitamin C transporter‐2 (SVCT‐2) functional expression in neuronal cells

Neuronal uptake of ascorbic acid (AA) in humans occurs via the human sodium‐dependent vitamin C transporter‐2 (hSVCT2; the product of the SLC23A2gene). Studies have shown that a significantly lower level of vitamin C is present in the blood plasma of patients with chronic neurological conditions including epilepsy. Therefore, studies focused on determining the molecular mechanisms involved in regulating hSVCT2 functional expression are vital for identifying potential therapeutic strategies to optimize vitamin C body homeostasis. Currently, little is known about the role of valproic acid (VPA), a drug used to treat epilepsy that also acts as a class I histone deacetylase inhibitor (HDACi), on AA uptake in neuronal systems. Thus, this study aims to investigate the effect of VPA on SVCT2 functional expression using human neuroblastoma SH‐SY5Y cells (in vitro) and mouse (in vivo) models. VPA (1mM) treatment up‐regulated the AA uptake and this increased uptake was accompanied by a marked increase in hSVCT2 protein and mRNA expression levels as well as SLC23A2 promoter activity in SH‐SY5Y cells. In addition, the protein and mRNA expression levels of specific protein‐1 (Sp1), a transcription factor that drives the basal activity of SLC23A2 promoter, were also markedly up‐regulated in VPA‐treated SH‐SY5Y cells. Further, knocking down the HDAC2, the predominant isoform in the neuronal system, significantly increased AA uptake and up‐regulated the hSVCT2 protein and mRNA expression levels in SH‐SY5Y cells. VPA administration (150 mg/kg body weight) to wild‐type (WT) mice displayed increased mouse (m)SVCT2 protein, mRNA and hnRNA expression in the brain. Together, our findings suggests that VPA up‐regulates the functional expression of SVCT2 and HDAC2 plays an essential role in neuronal AA uptake.

Effective Valproic Acid Treatment in Motor Function is Caused by Possible Mechanism of Elevated Survival Motor Neuron Protein Related with Splicing Factor Gene Expression in Spinal Muscular Atrophy

Effective Valproic Acid Treatment in Motor Function is Caused by Possible Mechanism of Elevated Survival Motor Neuron Protein Related with Splicing Factor Gene Expression in Spinal Muscular Atrophy

Different Effects of Valproic Acid on SLC12A2, SLC12A5 and SLC5A8 Gene Expression in Pediatric Glioblastoma Cells as an Approach to Personalised Therapy.

Valproic acid (VPA) is a histone deacetylase inhibitor with sex-specific immunomodulatory and anticancer effects. This study aimed to investigate the effect of 0.5 and 0.75 mM VPA on NKCC1 (SLC12A2), KCC2 (SLC12A5) and SLC5A8 (SLC5A8) co-transporter gene expressions in pediatric PBT24 (boy’s) and SF8628 (girl’s) glioblastoma cells. The SLC12A2, SLC12A5 and SLC5A8 RNA expressions were determined by the RT-PCR method. The SLC12A2 and SLC5A8 expressions did not differ between the PBT24 and SF8628 controls. The SLC12A5 expression in the PBT24 control was significantly higher than in the SF8628 control. VPA treatment significantly increased the expression of SLC12A2 in PBT24 but did not affect SF8628 cells. VPA increased the SLC12A5 expression in PBT24 and SF8628 cells. The SLC12A5 expression of the PBT24-treated cells was significantly higher than in corresponding SF8628 groups. Both VPA doses increased the SLC5A8 expression in PBT24 and SF8628 cells, but the expression was significantly higher in the PBT24-treated, compared to the respective SF8628 groups. The SLC5A8 expression in PBT24-treated cells was 10-fold higher than in SF8628 cells. The distinct effects of VPA on the expression of SLC12A2, SLC12A5 and SLC5A8 in PBT24 and SF8628 glioblastoma cells suggest differences in tumor cell biology that may be gender-related.

SARS-CoV-2 Infection, Sex-Related Differences, and a Possible Personalized Treatment Approach with Valproic Acid: A Review.

Sex differences identified in the COVID-19 pandemic are necessary to study. It is essential to investigate the efficacy of the drugs in clinical trials for the treatment of COVID-19, and to analyse the sex-related beneficial and adverse effects. The histone deacetylase inhibitor valproic acid (VPA) is a potential drug that could be adapted to prevent the progression and complications of SARS-CoV-2 infection. VPA has a history of research in the treatment of various viral infections. This article reviews the preclinical data, showing that the pharmacological impact of VPA may apply to COVID-19 pathogenetic mechanisms. VPA inhibits SARS-CoV-2 virus entry, suppresses the pro-inflammatory immune cell and cytokine response to infection, and reduces inflammatory tissue and organ damage by mechanisms that may appear to be sex-related. The antithrombotic, antiplatelet, anti-inflammatory, immunomodulatory, glucose- and testosterone-lowering in blood serum effects of VPA suggest that the drug could be promising for therapy of COVID-19. Sex-related differences in the efficacy of VPA treatment may be significant in developing a personalised treatment strategy for COVID-19.

Enhancement of cordycepin production from Cordyceps militaris culture by epigenetic modification.

Cordycepin (3'-deoxyadenosine) is a nucleoside analogue and biosynthesised by Cordyceps militaris, an entomopathogenic fungus. In this study, an epigenetic modifier was applied to static liquid cultures to enhance cordycepin production. C. militaris was cultured in a static liquid culture, and valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, was supplemented in order to modifying the epigenetic status. Gene regulatory network was explored to understand the molecular mechanisms underlying cordycepin production. 50 micromolar of VPA enhanced cordycepin production by 41.187% via the upregulation of 5'-nucleotidase, adenylate kinase, phosphorybosyltransferase, Cns1, Cns2, Cnsa3, and Cns4 of C. militaris for at least 2days after VPA treatment. The maximum production of cordycepin was 2,835.32 ± 34.35mg/L in 400mL-working volume. A scaled-up culture was established with a working volume of 10 L, which led to the slight decrease of cordycepin production. This might due to multifactorial effects, for instance limited aeration and an uneven dispersion of nutrients in the culture system. This scaled-up culture was still needed further optimization. The modification of epigenetic status by VPA significantly enhanced cordycepin production by altering key gene regulatory network of C. militaris. The strategy established in this study might be applicable to other microorganism culture in order to improving the production of bioactive compounds. This work aimed to enhance the production of cordycepin by modifying the epigenetic status of C. militaris, in which subsequently altered gene regulatory network of cordycepin biosynthesis pathway. The weekly supplementation of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, significantly improve cordycepin production over 40%, compared to the untreated control, and the gene regulatory network of C. militaris was also adapted.

The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation.

Background: Gemcitabine efficacy in pancreatic cancer is often impaired due to limited intracellular uptake and metabolic activation. Epi-drugs target gene expression patterns and represent a promising approach to reverse chemoresistance. In this study, we investigate the chemosensitizing effect of different epi-drugs when combined with gemcitabine in pancreatic cancer. Methods: Mouse KPC3 cells were used for all experiments. Five different epi-drugs were selected for combination therapy: 5-aza-2′-deoxycytidine, hydralazine, mocetinostat, panobinostat, and valproic acid (VPA). Treatment effects were determined by cell proliferation and colony forming assays. Expression of genes were assessed by real-time quantitative PCR. The most promising epi-drug for combination therapy was studied in immune competent mice. Intratumor changes were defined using NanoString PanCancer panel IO360. Results: All epi-drugs, except hydralazine, potentiated the gemcitabine response in KPC3 cells (range decrease IC50 value 1.7–2-fold; p < 0.001). On colony formation, the cytotoxic effect of 0.5 ng/mL gemcitabine was 1.4 to 6.3 times stronger (p < 0.01). Two out of three drug-transporter genes were strongly upregulated following epi-drug treatment (a range fold increase of 17–124 and 9–60 for Slc28a1 and Slc28a3, respectively; all p < 0.001). VPA combined with gemcitabine significantly reduced tumor size with 74% compared to vehicle-treated mice and upregulated expression of immune-related pathways (range pathway score 0.86–1.3). Conclusions: These results provide a strong rationale for combining gemcitabine with VPA treatment. For the first time, we present intratumor changes and show activation of the immune system. Clinical trials are warranted to assess efficacy and safety of this novel combination in pancreatic cancer patients.

Early postnatal handling alters social behavior, learning, and memory of pre- and postnatal VPA-induced rat models of autism in a context-based manner

Early life events are known to greatly affect brain development, cortical neurogenesis, and Hypothalamic-pituitary-adrenal activity. Mainly characterized by impairment in social communication, language, and cognitive development, autism spectrum disorder (ASD) refers to a class of neuropsychiatric disorders with numerous genetic and environmental risk factors. In the early handling (EH) method, daily separation of infants from their mother, physical touching, and exposure to a new environment occur. Here, we studied the effect of EH on Social interaction, learning, and memory in rats exposed pre-or post-natally to valproic acid (VPA). Gestational VPA exposure (600 mg/kg) led to some severe autistic-like traits, more notable in the social behavior of the male sex, along with unchanged to partially altered spatial learning and memory function and reduced avoidance memory. In comparison, while causing a sex-dependent increase in spatial memory, subcutaneous injection of VPA (400 mg/kg) in infancy resulted in limited adverse autistic features, including a decrease in males’ social preference, as well as reduced avoidance memory. The results indicated that neonatal handling significantly improved multiple social behavior and memory deficits in prenatally injected rats. In contrast, EH in rats receiving postnatal VPA elicited a restricted advantage on social novelty tendency; while negatively affecting some other social behavior criteria and spatial learning of males and encouraging sex-dependent repetitive behaviors in the social setting. The controversial influence of postnatal handling on juvenile rats of postnatal VPA treatment vs. prenatal VPA treatment opens up the potential for future research on the context-based consequence of early-life handling stress using different behavioral tasks and to benefit therapeutic procedures through understanding the sex- and age-specific neurobiology of short-term environmental manipulation in animal models of autism.

Comparative analysis of background EEG activity in juvenile myoclonic epilepsy during valproic acid treatment: a standardized, low-resolution, brain electromagnetic tomography (sLORETA) study

BackgroundBy definition, the background EEG is normal in juvenile myoclonic epilepsy (JME) patients and not accompanied by other developmental and cognitive problems. However, some recent studies using quantitative EEG (qEEG) reported abnormal changes in the background activity. QEEG investigation in patients undergoing anticonvulsant treatment might be a useful approach to explore the electrophysiology and anticonvulsant effects in JME.MethodsWe investigated background EEG activity changes in patients undergoing valproic acid (VPA) treatment using qEEG analysis in a distributed source model. In 17 children with JME, non-parametric statistical analysis using standardized low-resolution brain electromagnetic tomography was performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between untreated and treated conditions.ResultsVPA reduced background EEG activity in the low-frequency (delta-theta) bands across the frontal, parieto-occipital, and limbic lobes (threshold log-F-ratio = ±1.414, p < 0.05; threshold log-F-ratio= ±1.465, p < 0.01). In the delta band, comparative analysis revealed significant current density differences in the occipital, parietal, and limbic lobes. In the theta band, the analysis revealed significant differences in the frontal, occipital, and limbic lobes. The maximal difference was found in the delta band in the cuneus of the left occipital lobe (log-F-ratio = −1.840) and the theta band in the medial frontal gyrus of the left frontal lobe (log-F-ratio = −1.610).ConclusionsThis study demonstrated the anticonvulsant effects on the neural networks involved in JME. In addition, these findings suggested the focal features and the possibility of functional deficits in patients with JME.

The effect of valproic acid on SLC5A8 expression in gonad-intact and gonadectomized rat thymocytes.

BackgroundValproic acid (VPA) pharmacological mechanisms are related to the anti-inflammatory and anti-viral effects. VPA is a histone deacetylases inhibitor and serves a role in its immunomodulatory impacts. VPA has complex effects on immune cell’s mitochondrial metabolism. The SLC5A8 transporter of short fatty acids has an active role in regulating mitochondrial metabolism. The study aimed to investigate whether SLC5A8 expresses the sex-related difference and how SLC5A8 expression depends on gonadal hormones, VPA treatment, and NKCC1 expression in rat thymocytes.MethodsControl groups and VPA-treated gonad-intact and gonadectomized Wistar male and female rats were investigated (n = 6 in a group). The VPA 300 mg/kg/day in drinking water was given for 4 weeks. The SLC5A8 (Slc5a8 gene) and NKCC1 (Slc12a2 gene) RNA expressions were determined by the RT-PCR method.ResultsThe higher Slc5a8 expression was found in the gonad-intact males than respective females (p = 0.004). VPA treatment decreased the Slc5a8 expression in gonad-intact and castrated males (p = 0.02 and p = 0.03, respectively), and increased in gonad-intact female rats compared to their control (p = 0.03). No significant difference in the Slc5a8 expression between the ovariectomized female control and VPA-treated females was determined (p > 0.05). VPA treatment alters the correlation between Slc5a8 and Slc12a2 gene expression in thymocytes of gonad-intact rats.ConclusionVPA effect on the Slc5a8 expression in rat thymocytes is gender- and gonadal hormone-dependent.

Alterations of the Hippocampal Networks in Valproic Acid-Induced Rat Autism Model.

Autism Spectrum Disorder (ASD) is one of the most frequently diagnosed neurodevelopmental disorders, characterized among others by impairments in social interactions and repetitive behavior. According to one of the leading hypotheses about its origin, ASD is caused by the imbalance of excitatory and inhibitory circuit activity. ASD-related morphological and functional changes can be observed in several brain regions i.e., in the prefrontal cortex and the hippocampus. It is well-established that prenatal valproic-acid (VPA) exposure of rats on day 12.5 leads to neurodevelopmental alterations with autism-like clinical and behavioral symptoms. The aim of this study was to investigate potential changes in the excitability of neuronal networks and individual neurons of the hippocampus elicited by prenatal VPA treatment. As there are marked sex differences in ASD, offspring of both sexes were systematically tested, using two different age groups, to elucidate eventual differences in neurodevelopment after VPA treatment. Excitatory connections and long-term synaptic plasticity as well as intrinsic excitability of CA1 pyramidal cells were examined. Pregnant female Wistar rats received saline or 500 mg/kg VPA i. p. on gestation day 12.5. Brain slices of 6-week-old and 3-month-old offspring were investigated using extra- and intracellular electrophysiological techniques. Field potential- and whole-cell patch clamp recordings were carried out to measure network excitability and single cell activity in the CA1 region hippocampus. Enhanced excitability of hippocampal networks was detected in the 6-week-old VPA-treated male rats; however, this change could not be observed in 3-month-old males. Intrinsic excitability of single neurons, however, was increased in 3-month-old males. In 6-week-old treated females, the most prominent effect of VPA was an increase in voltage sag, to a similar degree to the neurons of the older age group. In 3-month-old females, a network excitability increase could be demonstrated, in a lesser degree than in younger males. It can be concluded, that VPA treatment had diverse effects on hippocampal excitability depending on the sex and the age of the animals. We found that certain alterations manifested in 6-week-old rats were compensated later, on the other hand, other changes persisted until the age of 3 months.

Oxidative post-translational modifications following valproic acid treatment are dependent upon cellular differentiative state

Oxidative post-translational modifications following valproic acid treatment are dependent upon cellular differentiative state

Effects of Low- and High-Dose Valproic Acid and Lamotrigine on the Heart in Female Rats

Epilepsy is a chronic neurological disease that affects more than 50 million people worldwide. Antiepileptic drugs (AEDs) are the mainstay of treatment for most patients with epilepsy. However, AEDs have been reported to be associated with adverse cardiac effects. In this study, it was aimed to investigate the possible cardiac effects of low-dose (LD) and high-dose (HD) treatment of valproic acid (VPA) and lamotrigine (LTG), which are commonly used AEDs, in rats without epilepsy. Rats were randomly grouped as control, LD-VPA, HD-VPA, LD-LTG, and HD-LTG. The cardiac effects of AEDs were evaluated using immunohistological, biochemical, and hemodynamic parameters. A dose-dependent increase in the intensity of caspase-3 staining was detected in the VPA and LTG groups. The intensity of connexin-43 and troponin-T staining in the VPA groups and desmin staining in the LTG groups was significantly reduced. Biochemically, HD-VPA and HD-LTG administrations caused a significant increase in MDA level in myocardial tissue. In addition, as a result of hemodynamic evaluations, cardiac functions were found to be affected and blood pressure increased in HD-LTG group. The results of present study support that VPA and LTG treatment can increase cardiac risk markers.

Evaluation of serum levels of asprosin and other metabolic profiles in patients with idiopathic tonic-clonic generalized epilepsy on treatment with valproic acid.

This cross-sectional research was undertaken to determine the serum levels of asprosin, a novel white adipose tissue-derived glucogenic adipokine, in epileptic patients on valproic acid treatment. Sixty-six patients diagnosed with idiopathic tonic-clonic generalized epilepsy were divided into three groups: those treated with valproic acid (n = 22), those treated with lamotrigine (n = 22), and twenty-two newly diagnosed or untreated patients. A control group was twenty-two, healthy volunteers with a similar distribution of gender and age. Body mass index (BMI) and fasting serum levels of asprosin, glucose, glycohemoglobin(HbA1c), insulin, and lipid profile were measured for both patients and control groups. Additionally, homeostasis model assessment for insulin resistance (HOMA-IR) was also calculated for the investigated groups. The mean BMI values and fasting serum levels of glucose, HbA1c, insulin, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride were much higher in subjects treated with valproic acid than those in the other study groups. Furthermore, a higher number of participants in the valproic acid group fulfilled the insulin resistance criterion (defined as HOMA-IR > 2.5) compared with those in other study groups. The mean fasting serum asprosin concentration was also significantly higher in the valproic acid group than in otherstudy groups. This was while the values of the study parameters were comparable in the healthy, un-treated, and lamotrigine groups. Our finding suggested that elevated asprosin level might be one of the pathological mechanisms involved in the development of obesity, insulin resistance, and metabolic disturbances related to valproic acid treatment.

The Effect of Coenzyme Q10 on Liver Injury Induced by Valproic Acid and Its Antiepileptic Activity in Rats.

Valproic acid (VPA) has toxic metabolites that can elevate oxidative stress markers, and the hepatotoxicity of VPA has been reported. Coenzyme Q10 (CoQ10) is one of the most widely used antioxidants. The effect of CoQ10 on epileptogenesis and VPA hepatotoxicity were examined. Rats were randomly divided into five groups: the control group received 0.5% methylcellulose by oral gavages daily and saline by intraperitoneal injection three times weekly. The PTZ group received 1% methylcellulose by gavages daily and 30 mg/kg PTZ by intraperitoneal injection three times weekly. The valproic acid group received 500 mg/kg valproic acid by gavage and 30 mg/kg PTZ, as above. The CoQ10 group received 200 mg/kg CoQ10 by gavages daily and 30 mg/kg PTZ, as above. The Valproic acid + CoQ10 group received valproic acid and CoQ10, as above. Results: CoQ10 exhibited anticonvulsant activity and potentiated the anticonvulsant effect of VPA. CoQ10 combined with VPA induced a more significant reduction in oxidative stress and improved the histopathological changes in the brain and liver compared to VPA treatment. In addition, CoQ10 reduced the level of toxic VPA metabolites. These findings suggest that the co-administration of CoQ10 with VPA in epilepsy might have therapeutic potential by increasing antiepileptic activity and reducing the hepatotoxicity of VPA.