Administration Of Valproic Acid Research Articles

The impact of valproic acid administration: Effects on the growth of tongue cancer cells

Background: Tongue cancer represents the predominant malignancy within the oral cavity (25-40% of squamous cell carcinoma), necessitating treatment modalities such as surgery, radiotherapy, and chemotherapy. Valproic acid, an antiepileptic medication, functions as a histone deacetylase inhibitor or activator of anti-tumor signaling pathways. Objective: To deepen our understanding of the effects of valproic acid on the viability, cytotoxicity, proliferation, and migration capabilities of HSC-3 cells. Method: This study employed an in vitro laboratory approach, exposing HSC-3 cells to valproic acid. The experimental groups included a negative control with culture media devoid of valproic acid, and treatment groups exposed to valproic acid at concentrations of 145 ppm, 180 ppm, and 355 ppm, respectively. Results: Significant differences (p-value <0.05) were observed between HSC-3 cells treated with valproic acid (145 ppm, 180 ppm, and 355 ppm) and the control group in terms of viability, cytotoxicity, proliferation, and migration. Reduced cell viability, increased cytotoxicity, and decreased proliferation were noted. Migration assays indicated suppressed migration of HSC-3 cells. Conclusion: In summary, this study reveals that valproic acid exerts substantial effects on various aspects of HSC-3 cell behavior. It decreases cell viability, enhances cytotoxicity, suppresses proliferation, and inhibits cell migration. These findings highlight the potential of valproic acid as a therapeutic agent for tongue cancer by targeting crucial cellular processes involved in cancer progression. Further research and clinical trials are essential to confirm these effects and explore their application in cancer treatment strategies. Novelty/Originality of this article:: This study shows valproic acid has potential as a therapeutic agent for tongue cancer by decreasing cell viability, increasing cytotoxicity, suppressing proliferation, and inhibiting migration of HSC-3 cells. These findings introduce a new application of valproic acid as an anticancer agent, expanding the use of antiepileptic drugs. This study opens up opportunities for developing more effective tongue cancer therapies and encourages further research and clinical trials to validate these findings

Oral edaravone ameliorates behavioral deficits and pathologies in a valproic acid-induced rat model of autism spectrum disorder

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

Peimine promotes microglial polarization to the M2 phenotype to attenuate drug-resistant epilepsy through suppressing the TLR4/NF-κB/HIF-1α signaling pathway in a rat model and in BV-2 microglia

Epilepsy is a chronic neurological disorder. Drug-resistant epilepsy (DRE) accounts for about one-third of epilepsy patients worldwide. Peimine, a main active component of Fritillaria, has been reported to show anti-inflammatory effects. However, its potential therapeutic role in DRE is not yet fully understood. In this work, a DRE rat model was established by injecting 1 μg kainic acid (KA), followed by a 250 mg/kg administration of valproic acid (VPA) from day 4 to 31. Rats were treated with different doses of peimine (2.5 mg/kg, 5 mg/kg and 10 mg/kg) daily from day 32 to 62. In vitro, BV-2 microglia were exposed to different doses of peimine (7.5 μg/ml, 15 μg/ml, and 30 μg/ml) in presence of LPS. The aim of this study was to investigate the potential therapeutic effects of peimine on DRE. The results showed that peimine efficiently suppressed the KA-induced epileptic behaviors of rats in a dose-dependent manner, as recorded by electroencephalography. Furthermore, peimine ameliorated hippocampal neuron injury in DRE rats, and promoted an M1-to-M2 microglial phenotype shift in a dose-dependent manner. Mechanistically, peimine inhibited the TLR4/NF-κB/HIF-1α signaling pathway both in vivo and in vitro. Additionally, peimine suppressed the apoptosis of primary neurons induced by LPS-treated microglia. In conclusion, peimine augments the microglial polarization towards an M2 phenotype by inhibiting the TLR4/NF-κB/HIF-1α signaling pathway, thereby attenuating DRE.

Effects of agmatine on radial-arm maze memory performance and autistic-like behaviors in a male rat model of autism.

Autism spectrum disorder (ASD) is the fastest-growing child neuropsychiatric condition. Cognitive dysfunctions such as memory impairments are experienced by patients along with social disturbances and repetitive/stereotypic movements. We have used the radial arm maze (RAM), for measurement of working and reference memory errors in an animal model of autism. In addition, the potential effects of agmatine, an endogenous NMDA antagonist, on RAM performance and autistic-like behaviors were assessed. Autism was modeled by valproic acid (VPA) administration at gestational Day 12.5. Autism-associated behaviors in male offspring were examined in an open field test (OFT) and three-chambered test (TCT) on postnatal days 50-51. Thereafter, the animals were trained in the RAM (PND 55) until they attained the criteria of 80% correct choices during five consecutive trials. Forty-eight hours after the acquisition of criteria, agmatine was injected 30 min before subsequent behavioral testing, which included the retention phase of the RAM, OFT, and TCT. VPA-treated and intact rats showed the same performance in RAM, and acute injection of agmatine rescued social and anxiety-like behavior induced by VPA without the effect on RAM. In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.

Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with fibrosis, which is responsible for severe complications. The phenotypic variability observed in RDEB siblings suggests that epigenetic modifications contribute to disease severity. Identifying epigenetic changes may help to uncover molecular mechanisms underlying RDEB pathogenesis and new therapeutic targets. To investigate histone acetylation in RDEB skin and to explore histone deacetylase inhibitors (HDACis) as therapeutic molecules capable of counteracting fibrosis and disease progression in RDEB mice. Acetylated histone levels were detected in human skin by immunofluorescence and in RDEB fibroblasts by ELISA. The effects of Givinostat and valproic acid (VPA) on RDEB fibroblast fibrotic behaviour were assessed by collagen-gel contraction assay, Western blot and immunocytofluorescence for α-smooth muscle actin, ELISA for released transforming growth factor-β1 (TGF-β1). RNA-seq was performed in HDACi- and vehicle-treated RDEB fibroblasts. VPA was systemically administered to RDEB mice, and effects on overt phenotype were monitored. Fibrosis was investigated in the skin using histological and immunofluorescence analyses. Eye and tongue defects were examined microscopically. Mass spectrometry proteomics was performed on skin protein extracts from VPA-treated RDEB and control mice. Histone acetylation decreases in RDEB skin and primary fibroblasts. RDEB fibroblasts treated with HDACis lowered fibrotic traits including contractility, TGF-β1 release, and proliferation. VPA administration to RDEB mice mitigated severe manifestations affecting eyes and paws. These effects were associated with fibrosis inhibition. Proteomic analysis of mouse skin revealed that VPA almost normalised protein sets involved in protein synthesis and immune response, processes linked to the increased susceptibility to cancer and bacterial infections observed in RDEB patients. Dysregulated histone acetylation contributes to RDEB pathogenesis by facilitating the progression of fibrosis. Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.

Management of the Drug-Drug Interactions Between Valproic Acid and Dolutegravir-A Case Study.

Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a male living with HIV who experienced a drastic reduction in dolutegravir trough concentrations a few weeks after starting valproic acid treatment as identified by therapeutic drug monitoring. Concomitantly, pharmacists recommended a supplementation of magnesium to improve insomnia. A 62-year-old man with HIV on antiretroviral therapy with dolutegravir and lamivudine recently added valproic acid to clonazepam and sertraline to treat severe sleep disturbances. An 84% reduction in dolutegravir trough concentrations was observed compared with the previous outpatient visit (418 versus 2714 ng/mL), with values close to the minimum effective drug concentration (300 ng/mL). Considering this, we strongly discourage the use of magnesium. We are confident that our findings can contribute to a better understanding of the clinical problems that infectious disease physicians encounter in their daily management of people with HIV and how therapeutic drug monitoring may add value in this context. This case also highlights the importance of multidisciplinary services for the optimal management of polypharmacy in people with HIV.

Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines.

The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have been partially attributed to the epigenetic disinhibition of the transcription repressor RE1-Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). Additionally, VPA changes post-traumatic brain injury (TBI) brain metabolism to create a neuroprotective environment. To address the interconnection of neuroprotection, metabolism, inflammation and REST/NRSF after TBI, we subjected C57BL/6N mice to experimental TBI and intraperitoneal VPA administration or vehicle solution at 15 min, 1, 2, and 3 days post-injury (dpi). At 7 dpi, TBI-induced an up-regulation of REST/NRSF gene expression and HDACi function of VPA on histone H3 acetylation were confirmed. Neurological deficits, brain lesion size, blood-brain barrier permeability, or astrogliosis were not affected, and REST/NRSF target genes were only marginally influenced by VPA. However, VPA attenuated structural damage in the hippocampus, microgliosis and expression of the pro-inflammatory marker genes. Analyses of plasma lipidomic and polar metabolomic patterns revealed that VPA treatment increased lysophosphatidylcholines (LPCs), which were inversely associated with interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) gene expression in the brain. The results show that VPA has mild neuroprotective and anti-inflammatory effects likely originating from favorable systemic metabolic changes resulting in increased plasma LPCs that are known to be actively taken up by the brain and function as carriers for neuroprotective polyunsaturated fatty acids.

Pre-treatment risk predictors of valproic acid-induced dyslipidemia in pediatric patients with epilepsy.

Background: Valproic acid (VPA) stands as one of the most frequently prescribed medications in children with newly diagnosed epilepsy. Despite its infrequent adverse effects within therapeutic range, prolonged VPA usage may result in metabolic disturbances including insulin resistance and dyslipidemia. These metabolic dysregulations in childhood are notably linked to heightened cardiovascular risk in adulthood. Therefore, identification and effective management of dyslipidemia in children hold paramount significance. Methods: In this retrospective cohort study, we explored the potential associations between physiological factors, medication situation, biochemical parameters before the first dose of VPA (baseline) and VPA-induced dyslipidemia (VID) in pediatric patients. Binary logistic regression was utilized to construct a predictive model for blood lipid disorders, aiming to identify independent pre-treatment risk factors. Additionally, The Receiver Operating Characteristic (ROC) curve was used to evaluate the performance of the model. Results: Through binary logistic regression analysis, we identified for the first time that direct bilirubin (DBIL) (odds ratios (OR) = 0.511, p = 0.01), duration of medication (OR = 0.357, p = 0.009), serum albumin (ALB) (OR = 0.913, p = 0.043), BMI (OR = 1.140, p = 0.045), and aspartate aminotransferase (AST) (OR = 1.038, p = 0.026) at baseline were independent risk factors for VID in pediatric patients with epilepsy. Notably, the predictive ability of DBIL (AUC = 0.690, p < 0.0001) surpassed that of other individual factors. Furthermore, when combined into a predictive model, incorporating all five risk factors, the predictive capacity significantly increased (AUC = 0.777, p < 0.0001), enabling the forecast of 77.7% of dyslipidemia events. Conclusion: DBIL emerges as the most potent predictor, and in conjunction with the other four factors, can effectively forecast VID in pediatric patients with epilepsy. This insight can guide the formulation of individualized strategies for the clinical administration of VPA in children.

Fluvoxamine Ameliorates the Damage to the Neuro-Behavioral Status of Rats Caused by the Administration of Valproic Acid by Preventing Cognitive Memory Deficits and Decreased Hippocampal Cellular Proliferation.

Fluvoxamine is a major antidepressant of the selective serotonin-reuptake inhibitor class, previously studied as a drug that improves cognitive memory by enhancing hippocampal cell division and proliferation. Valproic acid (VPA) is a commonly used antiepileptic drug and mood stabilizer that has negative effects on cognitive memory as itinhibits cellular division and proliferation in the hippocampus. This study assessed the protective effects of fluvoxamine treatment versus the memory impairment, decreased hippocampal cellular proliferation, and weight loss produced by VPA treatment. The cognitive memory of 40 male Sprague-Dawley rats was assessed by the novel object location (NOL) test. Immunostaining by Ki67 and glutathione peroxidase 1 (GPX-1) was performed to quantify the number of dividing cells in the subgranular zone (SGZ) of the dentate gyrus and to assess the antioxidant activity of different treatments, respectively. Results showed that the VPA group had fewer Ki67-positive cells than the control group (p < 0.001), indicating reduced hippocampal proliferation. In contrast, the VPA and fluvoxamine combination group showed increased proliferation (p < 0.001) compared to VPA alone. Notably, fluvoxamine treatment significantly differed in cell counts compared to other groups (p < 0.001). Fluvoxamine also attenuated the weight loss caused by VPA (p < 0.0001). Our data suggested that fluvoxamine therapy attenuated the VPA-induced decrease in SGZ cellular proliferation, memory, and weight in rats.

Abdominal migraine with acute watery diarrhea and dehydration: Successful treatment with Valproic acid in a pediatric case

Key Clinical MessageAbdominal migraine (AM) is a prevalent pediatric condition that rarely affects adults. Multiple diagnostic criteria have been established, but in general, AM is characterized by unprovoked episodes of acute central abdominal pain with migrainous characteristics and periods of respite. Recurrent stomach pain is a prevalent symptom globally, with a significant portion of cases falling under the category of functional gastrointestinal disorders (FGIDs) due to the absence of identified biological causes. There is a notable prevalence of migraines among individuals with a family history of the condition, indicating a genetic predisposition. A descriptive report has been prepared on the participant who had AM associated with acute watery diarrhea (AWD) on January 2023. The patient's parents had given written informed consent for publishing this case report. In this case report, we present the clinical scenario of a 12‐year‐old male child who experienced AM symptoms alongside a history of absence seizures. The child presented with episodes of abdominal pain and AWD. Despite extensive investigation and treatment, there was no improvement in abdominal pain. However, after 1 week of oral valproic acid administration, the patient remained symptom‐free during the follow‐up period. Dehydration, along with other factors, has been identified as a triggering factor for AM. Acute watery diarrhea has the potential to disrupt the normal functioning of the gastrointestinal system, and dehydration may lead to subsequent abdominal symptoms.

Effect of valproic acid on the formation and migration of cranial neural crest cells at the early developmental stages in rat embryos.

Cranial neural crest cells (NCCs) are critical for craniofacial development. The administration of valproic acid (VPA) to pregnant females causes craniofacial malformations in offspring. However, the in vivo influence of VPA on mammalian cranial NCCs remains unclear. In this study, we aimed to elucidate the developmental stage-specific effect of VPA on cranial NCCs through the administration of a single dose of VPA to pregnant rat females immediately prior to the formation of the cranial neural crest (NC). We performed whole-mount immunohistochemistry or in situ hybridization to examine localization changes of gene transcripts associated with the epithelial-mesenchymal transition of the cranial NC (i.e., cranial NCC formation) and cranial NCC migration. The results showed that Hoxa2 mRNA was abnormally detected and Sox9 mRNA expression was decreased in the midbrain-rhombomere (R) 1/2 NC, which forms cranial NCCs that migrate to the frontonasal mass (FNM) and branchial arch (BA) 1, through VPA administration, thus reducing the formation of SNAI2-positive NCCs. Hoxa2-positive NCCs were detected normally in BA2 and abnormally in FNM and BA1, which are normally Hox-free, implying VPA-induced abnormal cranial NCC migration. In vitro verification experiments using the whole embryo culture system revealed that midbrain-R4 NCC migration was abnormal. These results indicate that VPA reduces the formation/delamination of the midbrain-R1/2 NCCs in a developmental stage-specific manner and subsequently causes the abnormal migration of R4 NCCs, which suggests that the abnormal formation and migration of cranial NCCs contribute to the inhibition of axonal elongation in the trigeminal nerve and a reduction in head size.

Agmatine ameliorates valproic acid-induced depletion of parvalbumin-positive neuron.

Autism spectrum disorder (ASD) is a widespread neurodevelopmental disorder with unknown etiology. Dysfunction of several brain areas including the prefrontal cortex (PFC), hippocampus, and cerebellum is involved in cognitive and behavioral deficits associated with ASD. Several studies have reported a reduction in the number of parvalbumin-immunoreactive (PV+) neurons in brain areas of ASD patients and animal models such as a shank mutant mouse model and rodents receiving fetal valproic acid (VPA) administration. Developing therapeutic interventions that restore PV interneurons can be the future therapeutic approach to ASD. The present study examined the possible effect of agmatine (AG), an endogenous NMDA antagonist, on the number of PV+ neurons in a VPA animal model of autism. The therapeutic effects of AG in ameliorating ASD-like behaviors were previously reported in VPA rats. AG was gavaged at dosages of 0.001, 0.01, and 0.1mg/kg from gestational day (GD) 6.5 to 18.5, and the number of PV interneurons was analyzed by immunohistochemistry in the 1-month-old rats. Prenatal VPA (GD 12.5) or AG led to a decrease of PV neurons in the PFC, Cornu ammonia (CA1), and molecular layers (MLs) of the cerebellum. However, exposure to AG restored the PV population induced by VPA. AG may modify underlying neuronal mechanisms resulting in the increased survival or restoration of the PV population.

Carnitine in Alleviation of Complications Caused by Acute Valproic Acid Toxicity; an Exprimental Study on Mice.

Hyperammonemia and hepatotoxicity are well-known complications of valproic acid (VPA) poisoning. The objective of this study is to evaluate the potential role of carnitine in mitigating the adverse effects of acute VPA toxicity in mice. 54 male mice (25-30 g) were randomly assigned to one of three categories, including acute, sub-acute, and chronic poisoning. Each category contained 3 groups, each consisting of 6 mice (Group 1: control, Group 2: VPA treated, and Group 3: VPA + carnitine treated). The animals were sacrificed 24 hours after the initial injection, and their blood, liver, and brain samples were compared between groups of each category regarding liver function biomarkers, oxidative stress markers, ammonia level, and liver histopathologic changes using one-way ANOVA followed by Tukey's multiple comparison test. The administration of VPA increased the serum level of aspartate aminotransferase (AST) (p=0.003) and alanine aminotransferase (ALT) (p=0.001), as well as serum, and brain level of ammonia (p=0.0001 for both) in the intervention group. Elevated levels of lipid peroxidation and oxidative stress (p=0.0001 for both) in the liver tissue, decreased liver glutathione (p=0.0001) and ferric ion-reducing antioxidant power (FRAP) (p=0.0001), and histopathologic changes in the form of moderate to severe inflammation were observed. Administration of VPA + carnitine reduced AST (p=0.05) and ALT (p=0.01), increased the FRAP, reduced free oxygen radicals and liver lipid peroxidation (p=0.0001 for all), and decreased tissue damage in the form of moderate inflammation. The administration of carnitine was ineffective in reducing brain or plasma ammonia levels in acute VPA-treated animals (p = 0.0115). Although the administration of carnitine has been suggested as a protective remedy in cases of VPA toxicity, according to the present study, it did not have an antidotal effect and did not prevent encephalopathy or liver injury in acute VPA toxicity.

Evaluation of the Antigenotoxic Effect of Quercetin Against Antiepileptic Drug Genotoxicity by Comet Analysis

Valproic acid (VPA) is among the most commonly used antiepileptic drugs in childhood and adult epilepsy. Although VPA is well tolerated, it can cause life-threatening side effects. VPA has toxic and genotoxic effects. Antioxidants can reverse drugs' toxic and genotoxic effects. Therefore, our study aimed to evaluate the antigenotoxic protective effect of quercetin (QUE) against VPA genotoxicity by in vitro comet assay analysis method. Comet assay analysis was performed in five different groups. Group I; negative control (Sterile H2O), Group II; positive control (H2O2), Group III; VPA was applied in four different dose ranges, Group IV; QUE was applied in four different dose ranges, Group V; For the simultaneous combined administration of VPA and QUE, three different doses of VPA + four different doses of QUE were administered. Low-dose administration of QUE was more effective in ameliorating the damage caused by low-dose VPA (62.5 μg/ml) administration. It is seen that the genotoxic damage caused by the application of 125 μg/ml VPA can be eliminated by QUE at all doses. It was determined that different doses of QUE exhibited a significant antigenotoxic effect against damage caused by 125 µg/mL VPA (P&amp;lt;0.05). In our study, the curative effect of QUE on DNA damage was determined by in vitro comet analysis. Our analysis results showed that QUE ameliorates VPA-induced genetic damage.

Progression of albuminuria and podocyte injury in focal segmental glomerulosclerosis inhibited by enhanced glycosphingolipid GM3 via valproic acid

Focal segmental glomerulosclerosis, characterized by decreased numbers of podocytes in glomeruli, is a common cause of refractory nephrotic syndrome. Recently, we showed that enhanced glycosphingolipid GM3 expression after administration of valproic acid, an upregulator of ST3GAL5/St3gal5, was effective in preventing albuminuria and podocyte injury. We also revealed the molecular mechanism for this preventive effect, which involves GM3 directly binding nephrin that then act together in glycolipid-enriched membrane (GEM) fractions under normal conditions and in non-GEM fractions under nephrin injury conditions. Kidney disease is frequently referred to as a “silent killer” because it is often difficult to detect subjective symptoms. Thus, primary treatment for these diseases is initiated after the onset of disease progression. Consequently, the efficacy of enhanced levels of GM3 induced by valproic acid needs to be evaluated after the onset of the disease with severe albuminuria such as focal segmental glomerulosclerosis. Here, we report the therapeutic effect of enhanced GM3 expression induced via administration of valproic acid on albuminuria and podocyte injury after the onset focal segmental glomerulosclerosis in anti-nephrin antibody treated mice. Our findings suggest elevated levels of GM3 following treatment with valproic acid has therapeutic utility for kidney disease associated with severe albuminuria and podocyte injury.

Protective effect of valproic acid on ischemia-reperfusion induced spinal cord injury in a rat model

Purpose This study aims to determine the anti-inflammatory, antioxidant, and anti-apoptotic effects of valproic acid (VPA) on rat spinal cord tissue in ischemia-reperfusion (IR) injury model created by abdominal aorta occlusion. Materials and Methods Sprague Dawley rat (male sex) weighing 190–260 g divided into four experimental groups: control only underwent laparotomy, sham group, pre-IR injury (200 mg/kg dose), and post-IR injury (300 mg/kg) VPA. We measured serum levels of TNF-α, IL-6, IL-1β, IL-18, Total Oxidant Status (TOS) and Total Antioxidant Status (TAS), and serum Oxidative Stress Index (OSI) ratio, and tissue expression of Bax and Bcl2, Caspase3, and Bax/Bcl2 ratio. Results Serum IL-18 was higher in the sham than the control group(P = 0.001), and there were declines in the pre-IR treatment (P = 0.002) and the post-IR treatment when compared to sham (P = 0.001). Despite these reductions, IL-18 expression levels in both the pre- and post-IR treatment groups were higher than in the control group (P = 0.001 & P = 0.003). The favorable effects of pre-IR VPA administration on immunohistochemical biomarkers were superior to post-IR VPA administration. Conclusions Comparative analyses between prophylactic VPA administration and post-IR interventions revealed congruence in their anti-inflammatory and anti-apoptotic ramifications. VPA can reduce spinal cord IR injury in an aortic occlusion model of rats.

Revisiting Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients with Glioblastoma-Proteomic Alteration and Comparison Analysis with the Standard-of-Care Chemoirradiation.

Glioblastoma (GBM) is the most common brain tumor with an overall survival (OS) of less than 30% at two years. Valproic acid (VPA) demonstrated survival benefits documented in retrospective and prospective trials, when used in combination with chemo-radiotherapy (CRT). The primary goal of this study was to examine if the differential alteration in proteomic expression pre vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA as compared to standard-of-care CRT. The second goal was to explore the associations between the proteomic alterations in response to VPA/RT/TMZ correlated to patient outcomes. The third goal was to use the proteomic profile to determine the mechanism of action of VPA in this setting. Serum obtained pre- and post-CRT was analyzed using an aptamer-based SOMAScan® proteomic assay. Twenty-nine patients received CRT plus VPA, and 53 patients received CRT alone. Clinical data were obtained via a database and chart review. Tests for differences in protein expression changes between radiation therapy (RT) with or without VPA were conducted for individual proteins using two-sided t-tests, considering p-values of <0.05 as significant. Adjustment for age, sex, and other clinical covariates and hierarchical clustering of significant differentially expressed proteins was carried out, and Gene Set Enrichment analyses were performed using the Hallmark gene sets. Univariate Cox proportional hazards models were used to test the individual protein expression changes for an association with survival. The lasso Cox regression method and 10-fold cross-validation were employed to test the combinations of expression changes of proteins that could predict survival. Predictiveness curves were plotted for significant proteins for VPA response (p-value < 0.005) to show the survival probability vs. the protein expression percentiles. A total of 124 proteins were identified pre- vs. post-CRT that were differentially expressed between the cohorts who received CRT plus VPA and those who received CRT alone. Clinical factors did not confound the results, and distinct proteomic clustering in the VPA-treated population was identified. Time-dependent ROC curves for OS and PFS for landmark times of 20 months and 6 months, respectively, revealed AUC of 0.531, 0.756, 0.774 for OS and 0.535, 0.723, 0.806 for PFS for protein expression, clinical factors, and the combination of protein expression and clinical factors, respectively, indicating that the proteome can provide additional survival risk discrimination to that already provided by the standard clinical factors with a greater impact on PFS. Several proteins of interest were identified. Alterations in GALNT14 (increased) and CCL17 (decreased) (p = 0.003 and 0.003, respectively, FDR 0.198 for both) were associated with an improvement in both OS and PFS. The pre-CRT protein expression revealed 480 proteins predictive for OS and 212 for PFS (p < 0.05), of which 112 overlapped between OS and PFS. However, FDR-adjusted p values were high, with OS (the smallest p value of 0.586) and PFS (the smallest p value of 0.998). The protein PLCD3 had the lowest p-value (p = 0.002 and 0.0004 for OS and PFS, respectively), and its elevation prior to CRT predicted superior OS and PFS with VPA administration. Cancer hallmark genesets associated with proteomic alteration observed with the administration of VPA aligned with known signal transduction pathways of this agent in malignancy and non-malignancy settings, and GBM signaling, and included epithelial-mesenchymal transition, hedgehog signaling, Il6/JAK/STAT3, coagulation, NOTCH, apical junction, xenobiotic metabolism, and complement signaling. Differential alteration in proteomic expression pre- vs. post-completion of concurrent chemoirradiation (CRT) is present with the addition of VPA. Using pre- vs. post-data, prognostic proteins emerged in the analysis. Using pre-CRT data, potentially predictive proteins were identified. The protein signals and hallmark gene sets associated with the alteration in the proteome identified between patients who received VPA and those who did not, align with known biological mechanisms of action of VPA and may allow for the identification of novel biomarkers associated with outcomes that can help advance the study of VPA in future prospective trials.

The potential protective effect of liraglutide on valproic acid induced liver injury in rats: Targeting HMGB1/RAGE axis and RIPK3/MLKL mediated necroptosis.

Valproic acid (VPA) is a commonly used drug for management of epilepsy. Prolonged VPA administration increases the risk of hepatotoxicity. Liraglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist that act as a novel antidiabetic drug with broad-spectrum anti-inflammatory and antioxidant effects. This study tested the protective effect of liraglutide against VPA-induced hepatotoxicity elucidating the possible underlying molecular mechanisms. Forty adult male rats were allocated in to four equally sized groups; Group I (control group) received oral distilled water and subcutaneous normal saline for 2 weeks followed by subcutaneous normal saline only for 2 weeks. Group II (liraglutide group) received subcutaneous liraglutide dissolved in normal saline daily for 4 weeks. Group III (valproic acid-treated group) received sodium valproate dissolved in distilled water for 2 weeks. Group IV (Combined valproic acid & liraglutide treated group) received valproic acid plus liraglutide daily for 2 weeks which was continued for additional 2 weeks after valproic acid administration. The hepatic index was calculated. Serum AST, ALT, GGT, and ALP activities were estimated. Hepatic tissue homogenate MDA, GSH, SOD, HMGB1, MAPK, RIPK1, and RIPK3 levels were evaluated using ELISA. However, hepatic RAGE and MLKL messenger RNA expression levels using the QRT-PCR technique. Hepatic NF-κB and TNF-α were detected immunohistochemically. Results proved that liraglutide coadministration significantly decreased liver enzymes, MDA, HMGB1, MAPK, RIPK1 RIPK3, RAGE, and MLKL with concomitant increased GSH and SOD in comparison to the correspondent values in VPA-hepatotoxicity group. Conclusions: Liraglutide's protective effects against VPA-induced hepatotoxicity are triggered by ameliorating oxidative stress, inflammation, and necroptosis.

Evaluation of prenatal administration of valproic acid on the cerebellum of albino rat offspring

Introduction: Autism is a severe neurodevelopmental disorder of poorly understood etiology; which may be genetic, epigenetic or environmental. Valproic acid (VPA), the most widely used antiepileptic drug, has been reported to increase the risk of autism among the offspring of human mothers who are medicated with it during early pregnancy. Aim: The current work aimed to study the biochemical and histological changes in the cerebellum of the offspring of prenatally VPA treated rats. Materials and Methods: Twelve pregnant female albino rats were divided into two groups; control and VPA treated (50 mg/kg/day orally). The cerebellar sections of male offspring rats were subjected to biochemical tests (brain tissue Malondialdehyde (MDA), Superoxide dismutase (SOD), Tumor necrosis factor-alpha (TNF-α) and glutamate), histological examination, immunohistochemical analyses for the expression of glial fibrillary acidic protein (GFAP) and Bcl-2 associated X protein (Bax), and electro microscopical studies. Results: VPA caused significant elevation in the brain levels of oxidative stress marker MDA, proinflammatory cytokine TNF-α and excitatory neurotransmitter glutamate, with significant reduction in the level of brain antioxidant marker SOD, compared to the control group.

Transient plasticity response is regulated by histone deacetylase inhibitor in oxygen-glucose deprivation condition.

The pathological form of synaptic plasticity, ischemic long-term potentiation (iLTP), induced by oxygen and glucose deprivation (OGD), is implicated in the acute phase of stroke with the potentiation of N-methyl-D-aspartate receptor (NMDAR). While there has been widespread attention on the excitatory system, a recent study reported that γ-aminobutyric acid (GABA)ergic system is also involved in iLTP. Valproic acid (VPA), a histone deacetylase inhibitor, protects against ischemic damage. However, whether VPA regulates early phase plasticity in ischemic stroke remains unknown. The present study aims to investigate the potential role and mechanism of VPA in ischemic stroke. A brief exposure of OGD on the hippocampal slices and the induction of photothrombotic ischemia (PTI) were used as ex vivo and in vivo models of ischemic stroke, respectively. Using extracellular recordings, iLTP was induced in the hippocampal Schaffer collateral pathway following OGD exposure. VPA treatment abolished hippocampal iLTP via GABAA receptor enhancement and extracellular signal-regulated kinase (ERK) phosphorylation. Administration of VPA reduced brain infarct volume and motor dysfunction in mice with PTI. Moreover, VPA protected against ischemic injury by upregulating the GABAergic system and ERK phosphorylation, as well as by reducing of matrix metalloproteinase in a PTI-induced ischemic stroke model. Together, this study revealed the protection of VPA in ex vivo OGD-induced pathological form of neuroplasticity and in vivo PTI-induced brain damage and motor dysfunction through rescuing GABAergic deficiency and the pathological hallmarks of ischemia.