Effects Of Valproic Acid Treatment Research Articles

The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo

Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [111In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [177Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [177Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [177Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [177Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [177Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [177Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation.

P.548 The effects of clozapine on cognitive functioning in schizophrenia

Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17.Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd–29th day) or early adulthood (63rd–69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot.VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM.Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood.

Sleep Architecture in Valproate-Induced Nocturnal Enuresis in Primary School and Preschool Children

Nocturnal enuresis is one of the side effects of valproic acid treatment, and generally underdiagnosed by clinicians. Studies reported that a variable incidence of valproic acid-induced nocturnal enuresis is 2.2% to 24% with unclear explanations of the reasons behind valproic acid-induced nocturnal enuresis. A retrospective study was carried out on 260 children (aged 5-12 years) diagnosed with idiopathic epilepsy, treated with valproic acid to evaluate the nocturnal enuresis secondary to valproic acid, and to discuss the characteristics of their sleep architecture. Nocturnal enuresis was reported in 28 (10.7%) patients after a mean exposure time to valproate of 18.78±8.4 days. Nocturnal enuresis was significantly associated with younger age and serum level of valproate (P = .05). The polysomnographic study suggested that the underlying mechanism may be related to impaired sleep efficiency, frequent arousals, prolonged sleep latency, snoring, or increased sleep depth which may impair a child's ability to awaken to the sense of bladder fullness or contractions.Clinical trial registration: ClinicalTrials.gov identifiers: NCT04191863.

Evaluation of the Effects of Valproic Acid Treatment on Cell Survival and Epithelial-Mesenchymal Transition-Related Features of Human Gastric Cancer Cells.

Metastasis is the most important feature of gastric cancer accounting for more than 90% of tumor-related mortality. As one of the main modulators of epithelial-mesenchymal transition (EMT), histone deacetylase inhibitors (HDACI) are considered rational candidates for cancer therapy. Valproic acid (VPA) is a HDACI with reported controversial effects on the EMT. The main aim of the current study was to evaluate the effects of VPA treatment on cell survival and EMT-related features of human gastric cancer cells (AGS). Methyl-thiazoltetrazolium (MTT) assay was utilized to assess the effect of VPA on the proliferation rate of cells. Apoptotic cell death was detected with Annexin V/PI staining. Migratory ability of cells following VPA treatment was assessed using a Boyden chamber test. The expression of EMT markers in AGS cells was analyzed using quantitative real-time RT-PCR. Treatment with VPA significantly inhibited AGS cell proliferation compared with control. An increased rate of early and late apoptotic cells was observed following VPA exposure. It was demonstrated that VPA significantly diminished the cell migratory ability in AGS gastric cancer cells. Furthermore, treatment with VPA significantly decreased the expression of E-cadherin but increased the Vimentin expression. Our results showed that VPA induces apoptosis and inhibits the cell proliferation and the migratory ability of AGS gastric cancer cells and may prove useful in the development of therapeutic agents for human gastric cancer. However, these preliminary findings call for further investigations to clarify the precise molecular mechanisms by which VPA modulates the EMT process in a cell type-specific manner.

Frequency of valproic acid induced thrombocytopenia in epileptic patients in Tertiary Care Hospital, Faisalabad.

Epilepsy may be defined as recurrent abnormal neuronal discharge leading to seizures or periods of unusual behavior, sensations and sometimes loss of awareness. Valproic acid is a widely-used first-generation antiepileptic drug. It has good efficacy and pharmacoeconomic profiles. But adverse drug reactions are also reported. Thrombocytopenia is one of the adverse effects of valproic acid treatment. But local evidence was lacking. So we conducted this study to get local evidence. Objectives: To see the frequency of thrombocytopenia in epileptic patients taking valproic acid. Study Design: Descriptive cross sectional. Setting: Pediatric Department of DHQ Hospital Faisalabad. Period: 19-06-2017 to 19-12-2017. Material & Methods: 75 children were included. Then after taking informed consent patient’s blood sample was taken for complete blood count in standard vials and was sent to DHQ hospital pathology laboratory to diagnose thrombocytopenia as a count less than 150000cmm, where reports were verified by pathologist. All the data was analyzed by using SPSS version 20. Results: In this study, the mean age of patients was 6.59±3.15 years. There were 43 (57.3%) males and 32 (42.7%) females. In this study, 34 (45.3%) children had generalized type of epilepsy while 41 (54.7%) had focal type of epilepsy. The mean duration of valproic acid treatment was 3.15±2.82 years. The mean dose of valproic acid treatment was 38.40±6.07mg/kg. The mean platelet count 199602.87±58058.85mg/dl and 18 (24%) had thrombocytopenia while 57 (76%) did not develop thrombocytopenia. Conclusion: Thus the frequency of thrombocytopenia is low but still we will advise the patients to screen out themselves for bleeding or bruising.

The long term effect of valproic acid in lipid profiles among adult

Background Valproic acid is one of the most commonly used for the treatment of epilepsy, psychiatric disorders such as bipolar disorders, anxiety and prophylaxis migraine. Long-term use of valproic acid is related to metabolic disorders such as the increase of body weight and might be changes of lipid profiles which are contributed to cardiovascular events, however, these effects have not been fully determined. This study determines the effect of long term use valproic acid in triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels among adult. Methods An analytic observational study with the cross-sectional study design in sixty subjects (n = 31, with treatment duration less than 1 year, and n = 19, with treatment duration 1 year or more) who met the inclusion and exclusion criteria. The triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels were examined. The statistical difference of triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels from both groups was obtained from the analysis using the two-independent t-test. Results The most of demographic and clinical characteristics of subjects are similar in two groups, and there are no significant differences in triglyceride (p = 0,893), total cholesterol (p = 0,105), HDL cholesterol (p = 0,750), and LDL cholesterol (p = 0,200) levels on both groups. Conclusion There is no significant effect of valproic acid treatment for 1 year or more on triglyceride, total cholesterol, HDL cholesterol, and LDL cholesterol levels in adult.

Opposing Effects of Valproic Acid Treatment Mediated by Histone Deacetylase Inhibitor Activity in Four Transgenic X. laevis Models of Retinitis Pigmentosa

Opposing Effects of Valproic Acid Treatment Mediated by Histone Deacetylase Inhibitor Activity in Four Transgenic <i>X. laevis</i> Models of Retinitis Pigmentosa

Opposing Effects of Valproic Acid Treatment Mediated by Histone Deacetylase Inhibitor Activity in Four Transgenic X. laevis Models of Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinal degeneration (RD) that leads to blindness for which no treatment is available. RP is frequently caused by mutations in Rhodopsin; in some animal models, RD is exacerbated by light. Valproic acid (VPA) is a proposed treatment for RP and other neurodegenerative disorders, with a phase II trial for RP under way. However, the therapeutic mechanism is unclear, with minimal research supporting its use in RP. We investigated the effects of VPA on Xenopus laevis models of RP expressing human P23H, T17M, T4K, and Q344ter rhodopsins, which are associated with RP in humans. VPA ameliorated RD associated with P23H rhodopsin and promoted clearing of mutant rhodopsin from photoreceptors. The effect was equal to that of dark rearing, with no additive effect observed. Rescue of visual function was confirmed by electroretinography. In contrast, VPA exacerbated RD caused by T17M rhodopsin in light, but had no effect in darkness. Effects in T4K and Q344ter rhodopsin models were also negative. These effects of VPA were paralleled by treatment with three additional histone deacetylase (HDAC) inhibitors, but not other antipsychotics, chemical chaperones, or VPA structural analogues. In WT retinas, VPA treatment increased histone H3 acetylation. In addition, electron microscopy showed increased autophagosomes in rod inner segments with HDAC inhibitor (HDACi) treatment, potentially linking the therapeutic effects in P23H rhodopsin animals and negative effects in other models with autophagy. Our results suggest that the success or failure of VPA treatment is dependent on genotype and that HDACi treatment is contraindicated for some RP cases.SIGNIFICANCE STATEMENT Retinitis pigmentosa (RP) is an inherited, degenerative retinal disease that leads to blindness for which no therapy is available. We determined that valproic acid (VPA), currently undergoing a phase II trial for RP, has both beneficial and detrimental effects in animal models of RP depending on the underlying disease mechanism and that both effects are due to histone deacetylase (HDAC) inhibition possibly linked to autophagy regulation. Off-label use of VPA and other HDAC inhibitors for the treatment of RP should be limited to the research setting until this effect is understood and can be predicted. Our study suggests that, unless genotype is accounted for, clinical trials for RP treatments may give negative results due to multiple disease mechanisms with differential responses to therapeutic interventions.

Valproic acid (VPA) reduces sensorimotor gating deficits and HDAC2 overexpression in the MAM animal model of schizophrenia.

Evidence indicates that the disruption of epigenetic processes might play an important role in the development of schizophrenia symptoms. The present study investigated the role of histone acetylation in the development of sensorimotor gating deficits in a neurodevelopmental model of schizophrenia based on prenatal administration of methylazoxymethanol (MAM) at embryonic day 17. Valproic acid (VPA), an inhibitor of class I histone deacetylases, was administered (250 mg/kg, twice a day for 7 consecutive days) in early adolescence (23rd-29th day) or early adulthood (63rd-69th day) to rats. The effect of VPA treatment on the sensorimotor gating deficits induced by prenatal MAM administration was analyzed in adult rats at postnatal day 70 (P70). In addition, the effects of VPA administration (at the same doses) on MAM-induced changes in the levels of histone H3 acetylation at lysine 9 (H3K9ac) and histone deacetylase 2 (HDAC2) in the medial prefrontal cortex (mPFC) were determined at P70 using Western blot. VPA administration in either adolescence or early adulthood prevented the sensorimotor gating deficits induced by MAM. However, VPA administration in early adolescence or early adulthood did not alter H3K9ac levels induced by MAM. In contrast, VPA administration in either adolescence or adulthood prevented the increase in HDAC2 level evoked by MAM. Prenatal MAM administration impaired histone acetylation in the mPFC, which might be involved in the development of some of the neurobehavioral deficits (i.e., sensorimotor gating deficits) associated with schizophrenia. Blockade of HDAC2 might prevent the disruption of sensorimotor gating in adulthood.

Heterogeneity of HDAC3 expression and its modulation by valproic acid in glioblastoma cells.

e13038 Background: Glioblastoma (gbm) is a devastating malignancy and a therapeutic challenge. Our group and others have observed long-term gbm survivors treated with valproic acid (VPA), a histone deacetylase (HDAC) inhibitor. While in vitro studies of HDAC inhibitors have been promising, clinical trials and retrospective analyses have been disappointing. We hypothesize that HDAC3 may be a more specific target or treatment marker for gbm. Since limited data is available pertaining to HDAC3 and its modulation in gbm, our goals were to: 1) develop methods for determining HDAC3 expression and localization in gbm cells, 2) study HDAC3 heterogeneity among different gbm cell lines, including one in low passage, and 3) test the effect of VPA treatment on HDAC3 expression of gbm cells in vitro. Methods: Three established gbm cell lines (U-87, U-251 and E297), were cultured using standard technique. HeLa cells were used as the positive HDAC3 control. Cells were stained using 2 different antibodies, and analyzed using immunofluoresence microscopy (IFM), and Western blotting (with β-actin standards). IgG was used for negative isotype controls. Cell counts, viability, and H&amp;E staining for changes in morphology were also recorded. Lysates for Western blots were made from whole cells, nuclei, and cytoplasmic preparations. Band quantification was performed using the ImageJ software. Cells in exponential growth were treated for 48 hours with 10 mM VPA, and compared to untreated cells. Results: Untreated cells studied for HDAC3 using IFM showed nuclear and some cytoplasmic staining in all 4 lines, which varied according to cell type and morphology. Western blot analysis confirmed the variability of HDAC3 expression seen by IFM. The effect of VPA treatment on gbm HDAC3 expression (cytoplasmic and nuclear) was seen to be highly variable, ranging from marked down-modulation in some gbm cells, to minimal effect in others. Conclusions: These data provide the groundwork for studying HDAC3 levels in patients undergoing therapy with HDAC inhibitors. The effect of VPA on the HDAC3 expression of gbm cells is heterogeneous; individualized assessment of such effect will be necessary in delineating any subset of patients that may respond to VPA treatment.

Valproic acid does not affect decreased insulin secretion in WFS1‐deficient pancreatic islets

Wolfram syndrome, an autosomal recessive disorder characterized by juvenile‐onset diabetes mellitus and optic atrophy, is caused by mutations in the wolframin (WFS1) gene. WFS1 negatively regulates endoplasmic reticulum (ER) stress signalling and therefore have a role in the pathogenesis of diabetes. Valproic acid (VPA), a widely used anticonvulsant and mood‐stabilizing drug, normalized the glucose intolerance in Wfs1 mutant mice, but had no effect on the course of glucose tolerance in wild‐type (WT) mice. The aim of this study was to investigate insulin secretion in isolated pancreatic islets of WFS1‐deficient (Wfs1KO) mice and also evaluate insulin secretion in the presence of VPA. In addition, the content of proinsulin in the isolated islets was measured. In general Wfs1KO pancreatic islets secreted less insulin compared to WT and Wfs1HZ islets. Differences in proinsulin amount were not statistically significant although there was a trend that Wfs1KO had an increased level of proinsulin. We found significantly reduced insulin secretion in Wfs1 mutants and no effect of VPA treatment.This study was supported by the Frontiers of Functional Genomics and by The European Regional Development Fund.

Effect of valproic acid treatment on penile structure in prepubertal rats

The aim of this study was to determine the histological effects of valproic acid (VPA) on the penis in prepubertal rats. Twelve male Wistar rats (21-24 days old) were divided equally into 2 experimental groups, and given tap water (control group) or 300mg/kg/day VPA via gavage for 30 days. After the penes had been harvested, the antiangiogenic and antifibrogenic properties of VPA were evaluated immunohistochemically using vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), transforming growth factor-beta 1 (TGF-β1) and Masson's trichrome staining. Apoptosis was determined by caspase-3 and caspase-9 immunoreactions. Results were expressed as histochemical score (HSCORE), a semi-quantitative analysis for the intensity of immunohistochemical reactivity. Immunohistochemical HSCORE decreased for VEGF and TGF-β1 staining and increased for iNOS staining in rats treated with VPA compared with the control group. Intensities of caspase-3 and caspase-9 labeling were also significantly increased by administration of VPA. Masson's trichrome staining exhibited a fairly diminished level of collagen in the corpus cavernosum of rats treated with VPA. In the light of these results, the administration of VPA from prepuberty to adulthood led to increased apoptosis and deterioration of the smooth muscle/collagen ratio in rat's corpus cavernosum.

Effect of valproic acid treatment on copper availability in adult epileptic patients

Objectives In rats a significant increase of the copper biliary excretion is produced by valproic acid administration, however, a conclusive study on the possible appearance of copper deficiency in humans during treatment with this drug has still not been carried out. Design and methods In 101 adult epileptic patients treated in monotherapy ( n = 75) and polytherapy ( n = 26) with valproic acid, and 50 healthy controls, were determined serum copper, immunoreactive ceruloplasmin and its oxidase activity against o-dianisidine, in order to calculate the specific oxidase activity (activity per unit mass of enzyme protein) and copper/ceruloplasmin ratio. Results Specific oxidase activity of ceruloplasmin and copper/ceruloplasmin ratio were significantly lower in the groups of patients treated with valproic acid than in the controls. Significant correlations were obtained between both biochemical variables ( p < 0001). In 38% of the patients treated in mono or polytherapy, the specific oxidase activities of ceruloplasmin were smaller than the estimated lower limit of reference. Conclusions These results, possible due to a diminished copper content of the circulating ceruloplasmin, suggest that marginal or moderate copper deficiency may have a substantial prevalence among patients treated with valproic acid.

64 VALPROIC ACID ENHANCES IN VITRO DEVELOPMENT OF SOMATIC CELL NUCLEAR TRANSFER EMBRYOS IN PIGS

Epigenetic modification influences reprogramming and subsequent development of somatic cell nuclear transfer embryos. Such modification includes an increase of histone acetylation and a decrease of DNA methylation in transferred donor nuclei. Histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) and valproic acid (VPA) have been known to maintain high cellular levels of histone acetylation. Hence, the treatment of HDACi to NT embryos may increase efficiency of cloning. Indeed, TSA treatment has significantly enhanced the developmental competence of nuclear transfer embryos in several species including pigs (Zhang et al. 2007 Cloning Stem Cells 9, 357-363; Li et al. 2008 Theriogenology 70, 800-808). Valproic acid, another type of HDACi, has often been used to assist reprogramming of somatic cells into induced pluripotent stem cells in mice. In the present study, we tested the potency of VPA compared with TSA on the enhancement of in vitro development in porcine nuclear transfer embryos. Reconstructed embryos were produced by transferring nuclei of adult ear skin fibroblasts into enucleated oocytes. After electrical activation, these embryos were cultured in PZM-3 containing no HDACi (control), 5 mM VPA, or 50 nM TSA for 24 h, and another 5 days thereafter without HDACi. At least 3 replicates were conducted for the following experiments. The rates of cleavage were not different among the VPA, TSA, and control groups. However, the rate of blastocyst development was significantly higher (P &lt; 0.05) in embryos treated with VPA than in those treated with TSA and without HDACi (125/306, 40.8% v. 94/313, 30.0% v. 80/329, 24.3%). Differential staining of inner cell mass (ICM) and trophectoderm (TE) also supported the beneficial effect of VPA treatment in NT embryos. Compared with the control group, the number of TE cells was significantly increased (P &lt; 0.05) in the VPA and TSA treatment groups (79.3 ± 7.4 v. 74.6 ± 9.2 v. 40.0 ± 6.7). Moreover, VPA treatment significantly increased (P &lt; 0.05) the number of ICM cells compared with the control (15.6 ± 1.7 v. 10.8 ± 2.6), whereas no differences were observed between the TSA treatment and control group (12.9 ± 3.0 v. 10.8 ± 2.6). The present study demonstrates that VPA enhances in vitro development of nuclear transfer embryos, in particular by an increase of blastocyst formation and the number of ICM cells, suggesting that VPA may be more potent than TSA in supporting developmental competence of cloned embryos. However, long-term effects of different HDACi in the development of nuclear transfer embryos, including any adverse outcome from destabilizing epigenetic condition, remain to be determined by further in vivo embryo transfer studies.

Effect of valproic acid treatment on body composition, leptin and the soluble leptin receptor in epileptic children

The aim of the study was to determine the influence of valproic acid (VPA) treatment on leptin, the soluble leptin receptor (sOB-R), the sOB-R/leptin ratio, body composition and insulin resistance in epileptic children. A cross-sectional cohort study was conducted at the Medical University Innsbruck, Austria. Children >6 years with idiopathic epilepsy and antiepileptic drug therapy since at least six months were eligible. Leptin concentration, the sOB-R, the sOB-R/leptin ratio, body composition and glucose homeostasis were determined. 87 children (median [range] age 12.8 years [6.0-18.6]) were on treatment with VPA, 55 (12.3 years [6.4-18.3]) on other AEDs, comprising the non-VPA group. VPA-treated children had higher leptin concentrations, body-mass-index standard-deviation score (SDS), body fat (each p<0.001), serum insulin concentrations (p=0.014) and homeostasis model assessment (HOMA) index (p=0.009), as well as a lower sOB-R/leptin ratio (p<0.001) when compared to the non-VPA group. Overweight VPA-treated children showed lower sOB-R concentrations and a lower sOB-R/leptin ratio (each p<0.001) as well as higher body fat and leptin levels (each p<0.001) compared to lean VPA-treated children. VPA monotherapy was associated with higher body weight, body fat and serum leptin concentrations as well as impaired glucose homeostasis. Low sOB-R concentrations and a low sOB-R/leptin ratio in overweight VPA-treated patients might contribute to disturbances in glucose homeostasis and to the development of the metabolic syndrome in these children later in life.

Effect of valproic acid treatment on body composition, leptin and soluble leptin receptor in epileptic children

Effect of valproic acid treatment on body composition, leptin and soluble leptin receptor in epileptic children

0107 Determining the effect of valproic acid treatment on factor VIII, factor IX, von Willebrand factor, protein C, protein S, antithrombin-III, serum lipids and lipoprotein (A)

0107 Determining the effect of valproic acid treatment on factor VIII, factor IX, von Willebrand factor, protein C, protein S, antithrombin-III, serum lipids and lipoprotein (A)

Effect of valproic acid treatment on spike-wave discharge patterns during sleep and wakefulness.

7 patients suffering from absences were recorded before antiepileptic treatment, in the early phase of valproate monotherapy and after having reached steady state. Recordings made with the Oxford-Medilog 4-channel cassette recorder were analyzed visually as well as by a computerized s-w pattern recognition approach, the latter facilitating quantification of pattern characteristics (number, amplitudes and duration of spikes and waves). Measurements were made separately for epochs of wakefulness and sleep. Compared to the premedication phase the amount of s-w discharges in 24 h showed an average reduction of more than 90%. For the majority of the patients, 24-hour discharge profiles showed a maximum in the early morning. Duration and amplitude of both spike and wave elements was higher during sleep. For the waking state, the ratio wave amplitude/spike amplitude was found to be increased under medication.