Administration Of Valproic Acid Research Articles

Comparison of EEG analysis systems during lidocaine-induced seizure activity and administration of valproic acid in rabbits

Comparison of EEG analysis systems during lidocaine-induced seizure activity and administration of valproic acid in rabbits

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells.

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

Resveratrol prevents oxidative damage and loss of sperm motility induced by long-term treatment with valproic acid in Wistar rats

Valproic acid (VPA) is a drug widely use for the treatment of epilepsy in both children and adults. Evidence suggests that long-term use of VPA may lead to an impairment in the male reproductive function. Oxidative stress is considered to play a major role in VPA associated toxicity. In the present work, we demonstrated that the natural antioxidant compound resveratrol (RSV) can be use to prevent VPA oxidative damage. Wistar rats treated with VPA (400mgkg−1) by gavage for 28days showed decrease in sperm motility accompanied by increase in oxidative damage to lipids and proteins. Additionally, VPA administration leaded to depletion of reduced glutathione and decrease in total antioxidant potential in testes and epididymides of Wistar rats. The co-administration of RSV (10mgkg−1) efficiently prevented VPA pro-oxidant effects. In summary, RSV was shown to protect the reproductive system from the damage induced by VPA. Altogether, our data strongly suggests that RSV administration might be a valuable strategy to minimize reproductive impairment in patients requiring long-term VPA treatment.

Protective effect of vitamin E on sperm motility and oxidative stress in valproic acid treated rats

Long-term administration of valproic acid (VPA) is known to promote reproductive impairment mediated by increase in testicular oxidative stress. Vitamin E (VitE) is a lipophilic antioxidant known to be essential for mammalian spermatogenesis. However, the capacity of this vitamin to abrogate the VPA-mediated oxidative stress has not yet been assessed. In the current study, we evaluated the protective effect of VitE on functional abnormalities related to VPA-induced oxidative stress in the male reproductive system. VPA (400 mg kg−1) was administered by gavage and VitE (50 mg kg−1) intraperitoneally to male Wistar rats for 28 days. Analysis of spermatozoa from the cauda epididymides was performed. The testes and epididymides were collected for measurement of oxidative stress biomarkers. Treatment with VPA induced a decrease in sperm motility accompanied by an increase in oxidative damage to lipids and proteins, depletion of reduced glutathione and a decrease in total reactive antioxidant potential on testes and epididymides. Co-administration of VitE restored the antioxidant potential and prevented oxidative damage on testes and epididymides, restoring sperm motility. Thus, VitE protects the reproductive system from the VPA-induced damage, suggesting that it may be a useful compound to minimize the reproductive impairment in patients requiring long-term treatment with VPA.

Anticancer effects of valproic acid on esophageal stem-like carcinoma cells

Valproic acid (VPA) is a histone deacetylase inhibitor that has been an object of interest to clinicians for its promising potency in cancer therapy, as it induces apoptosis and differentiation, and enhances of chemotherapy sensitivity. Esophageal squamous cell carcinoma (ESCC) is a malignant disease with growing incidence and low survival rate. Due to limited information on VPA activity in ESCC cells, we aimed to determine effects of VPA on chemotherapy responsiveness and expression of malignant markers in ESCC stem-like cells. Upon coadministration of non-toxic VPA + cisplatin (DDP), paclitaxel and 5-fluorouracil, viability of KYSE30 cells was assessed, and induced apoptosis was evaluated by DAPI staining, DNA laddering and flow cytometry. In addition, real time RT-PCR was performed to study changes in the expression of P21, CD44 and BMI-1 upon treatments. MTT test demonstrated that VPA significantly (P ＜ 0.05) increased toxicity of DDP, which was confirmed by DNA laddering, flow cytometry analysis and significant (P ＜ 0.05) overexpression of P21. Moreover, real time RT-PCR results indicated significant (P ＜ 0.05) down regulation of CD44 and BMI-1 after VPA administration. Present attempt provided evidence, for the first time, that VPA not only improved responsiveness of esophageal stem-like cancer cells to DDP, also negatively regulated cancer stem cells markers in these cells.

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Recent studies have demonstrated that Wnt signaling and mTOR signaling play important roles in the pathogenesis of ASD. However, the relationship of these two signaling pathways in ASD remains unclear. We assessed this question using the valproic acid (VPA) rat model of autism. Our results demonstrated that VPA exposure activated mTOR signaling and suppressed autophagy in the prefrontal cortex, hippocampus and cerebellum of autistic model rats, characterized by enhanced phospho-mTOR and phospho-S6 and decreased Beclin1, Atg5, Atg10, LC3-II and autophagosome formation. Rapamycin treatment suppressed the effect of VPA on mTOR signaling and ameliorated the autistic-like behaviors of rats in our autism model. The administration of VPA also activated Wnt signaling through up-regulating beta-catenin and phospho-GSK3beta. Suppression of the Wnt pathway by sulindac relieved autistic-like behaviors and attenuated VPA-induced mTOR signaling activation in autistic model rats. Our results demonstrate that VPA exposure sequentially activates Wnt signaling and mTOR signaling in rats. Suppression of the Wnt signaling pathway relieves autistic-like behaviors partially by deactivating the mTOR signaling pathway in VPA-exposed rats.

Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder

BackgroundBipolar disorder (BD) is a severe and debilitating psychiatric disorder. However, the precise biological basis remains unknown, hampering the search for novel biomarkers. We performed a metabolomics analysis to discover novel peripheral biomarkers for BD. MethodsWe quantified serum levels of 116 metabolites in mood-stabilized male BD patients (n=54) and age-matched male healthy controls (n=39). ResultsAfter multivariate logistic regression, serum levels of pyruvate, N-acetylglutamic acid, α-ketoglutarate, and arginine were significantly higher in BD patients than in healthy controls. Conversely, serum levels of β-alanine, and serine were significantly lower in BD patients than in healthy controls. Chronic (4-weeks) administration of lithium or valproic acid to adult male rats did not alter serum levels of pyruvate, N-acetylglutamic acid, β-alanine, serine, or arginine, but lithium administration significantly increased serum levels of α-ketoglutarate. ConclusionsThe metabolomics analysis demonstrated altered serum levels of pyruvate, N-acetylglutamic acid, β-alanine, serine, and arginine in BD patients. General significanceThe present findings suggest that abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism play a role in the pathogenesis of BD.

Safety and efficacy of valproic acid treatment in SCA3/MJD patients

BackgroundSpinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is one of 10 known polyglutamine (polyQ) diseases. In Drosophila and rat models of polyQ diseases, histone deacetylation (HDAC) inhibitors improved locomotor function and survival time by increasing histone acetylation levels and modulating gene expression. Valproic acid (VPA) is a pan-HDAC inhibitor used clinically to treat bipolar and seizure disorders. We evaluated the clinical safety and efficacy of VPA treatment for SCA3/MJD patients. MethodsFirst, a randomized, open-label, dose-escalation method was used to evaluate tolerance to single-dose VPA administration in 12 SCA3/MJD patients. Patients were randomly assigned to three groups of four subjects, each with an oral dosage of 400 mg, 600 mg, or 800 mg (twice daily (bid) for one day). VPA was well-tolerated for one-dose by all patient groups. Second, a randomized, double-blind, placebo-controlled, dose-controlled study evaluated the safety and efficacy of multi-dose VPA (oral administration, twice daily (bid) for 12 weeks) in 36 SCA3/MJD patients. Patients received either low-dose VPA (800 mg/day), high-dose VPA (1200 mg/day), or placebo (n = 12 subjects per group). Symptoms were evaluated using the Scale for Assessment and Rating of Ataxia (SARA). ResultsMulti-dose VPA treatment improved SARA measures of locomotor function. Major adverse effects included dizziness and loss of appetite. ConclusionsVPA is a potentially beneficial agent for the treatment of SCA3/MJD. These results also provide insight into possible future therapeutics for polyQ diseases.

Valproic acid ameliorates olfactory dysfunction in APP/PS1 transgenic mice of Alzheimer's disease: Ameliorations from the olfactory epithelium to the olfactory bulb

Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Alzheimer's disease (AD) and mild cognitive impairment, pointing to the progression to dementia. Recent studies have revealed that valproic acid (VPA) has neuroprotective effects in rodent models of AD. In this study, we investigated the effects of VPA on olfactory dysfunction of APP/PS1 double transgenic mouse models of AD. After continuous treatment with a 100mg/kg daily dose of VPA for 3months, APP/PS1 mice showed improved olfactory performances. In agreement with the behavioral findings, VPA treatment reduced amyloid β (Aβ) burden in the olfactory epithelium (OE) of transgenic mice. And, VPA increased epithelial thickness of the olfactory mucosa through decreased cell apoptosis and increased cell proliferation. In the olfactory bulb (OB), VPA administration also reduced senile plaques and levels of soluble and insoluble Aβ42 peptides. Besides, VPA promoted the increase of mitral cells and decrease of neurofilament immunostaining. In hence, VPA treatment completely improved the olfactory performances and prevented degenerative changes of the OE and OB. Our study raises the possibility of AD diagnosis by OE biopsy. Moreover, VPA may provide a novel therapeutic strategy for the treatment of olfactory dysfunction in AD patients.

Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: Influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs

BackgroundCarbamazepine is one of the three most frequently prescribed antiepileptic drugs in pregnancy. However, data relating to both carbamazepine and carbamazepine-10,11-epoxide transplacental passage remain sparse. Material and methodsWe have analysed in a cohort of 114 women carbamazepine and carbamazepine-10,11-epoxide levels in maternal and umbilical cord serum at birth during 25 years retrospectively. The carbamazepine maternal apparent oral clearance, ratio of the umbilical cord/maternal level and ratio of the carbamazepine-10,11-epoxide/carbamazepine ratio were estimated. The influence of co-medication with valproic acid or enzyme-inducing antiepileptic drugs was evaluated. ResultsThe maternal carbamazepine levels varied from 0.6 to 11.8mg/L (carbamazepine-10,11-epoxide 0.1–2.5mg/L) and in umbilical cord between 0.1 and 10.5mg/L (carbamazepine-10,11-epoxide 0.1–2.2mg/L). The ratio the of umbilical cord/maternal level of carbamazepine ranged from 0.03 to 2.23 (median 0.80) and of carbamazepine-10,11-epoxide between 0.17 and 2.00 (median 0.83). Concomitant administration with enzyme inducers significantly increased the maternal apparent oral clearance by approximately 50% and co-administration with valproic acid approximately by 70%. Combination with valproic acid significantly increased the rate of carbamazepine-10,11-epoxide to the parent drug both in maternal serum (by approximately 80%) and in umbilical cord (by 100%). ConclusionsThe data showed the wide interindividual variability of the ratio of the umbilical cord/maternal level of both carbamazepine and carbamazepine-10,11-epoxide. It is the first study showing the significant increase of the ratio of umbilical cord/maternal level of carbamazepine-10,11-epoxide and carbamazepine-10,11-epoxide/carbamazepine ratio not only in maternal serum but also in umbilical cord in addition of valproic acid. The present study demonstrates that a concomitant administration of enzyme-inducing antiepileptics and valproic acid increases the maternal apparent oral clearance of carbamazepine significantly.

Oct4 transcription factor in conjunction with valproic acid accelerates myelin repair in demyelinated optic chiasm in mice

Multiple sclerosis is a demyelinating disease with severe neurological symptoms due to blockage of signal conduction in affected axons. Spontaneous remyelination via endogenous progenitors is limited and eventually fails. Recent reports showed that forced expression of some transcription factors within the brain converted somatic cells to neural progenitors and neuroblasts. Here, we report the effect of valproic acid (VPA) along with forced expression of Oct4 transcription factor on lysolecithin (LPC)-induced experimental demyelination.Mice were gavaged with VPA for one week, and then inducible Oct4 expressing lentiviral particles were injected into the lateral ventricle. After one-week induction of Oct4, LPC was injected into the optic chiasm. Functional remyelination was assessed by visual-evoked potential (VEP) recording. Myelination level was studied using FluoroMyelin staining and immunohistofluorescent (IHF) against proteolipid protein (PLP). IHF was also performed to detect Oct4 and SSEA1 as pluripotency markers and Olig2, Sox10, CNPase and PDGFRα as oligodendrocyte lineage markers.One week after injection of Oct4 expressing vector, pluripotency markers SSEA1 and Oct4 were detected in the rims of the 3rd ventricle. LPC injection caused extensive demyelination and significantly delayed the latency of VEP wave. Animals pre-treated with VPA+Oct4 expressing vector, showed faster recovery in the VEP latency and enhanced myelination. Immunostaining against oligodendrocyte lineage markers showed an increased number of Sox10+ and myelinating cells. Moreover, transdifferentiation of some Oct4-transfected cells (GFP+ cells) to Olig2+ and CNPase+ cells was confirmed by immunostaining.One-week administration of VPA followed by one-week forced expression of Oct4 enhanced myelination by converting transduced cells to myelinating oligodendrocytes. This finding seems promising for enhancing myelin repair within the adult brains.

High-calorie diet inflates steatogenic effects of valproic acid in mice

Valproic acid (VPA) is an anti-epileptic drug used in patients with convulsive seizures and psychic disorders. Despite its therapeutic use, VPA administration is associated with several side effects of which hepatosteatosis (lipid deposition in liver >10% of organ weight) is of concern. Recently, the consumption of western-type diet rich in fat and simple sugar has increased, the pathological consequences of which has been linked to the escalating incidence of metabolic disorders. The hypothesis of the study is that the metabolic stress induced by high-calorie diet may potentiate VPA-induced hepatosteatosis. Two groups of Swiss Mus musculus male mice weighing 25–35 g were fed either normal chow or high fat and high fructose diet (HFFD) and maintained for 30 days. On the 16th day of the experiment, VPA (100 mg/kg bw) administration was initiated in one set of animals from each group and the other set was left without VPA treatment. Assays were done in the hemolysate, plasma and liver tissue of mice after the experimental period. Deregulated lipid metabolism, loss of insulin sensitivity, enhanced CYP2E1 activity and oxidative damage, and diminution of cellular antioxidants were observed in animals that received HFFD and VPA. HFFD-fed mice are sensitized to VPA toxicity than the normal chow-fed counterparts. The results of this study show that preformed metabolic derangements due to high-energy diet may infuriate VPA-induced hepatosteatosis and insulin resistance.

Case: Valproat-Induced Hyperammonemic Encephalopathy

Valproate induced hyperammonemic encephalopathy (VHE) is a severe adverse effect of medicine. An epileptic patient with an acute hyperammonemia after the addition of valproic acid to his treatment presented with acute mental status changes consistent with encephalopathy. Notably, plasma ammonia level was 2 times of the upper limit, despite normal liver function tests. Plasma valproic acid level was in the therapeutic range. His symptoms resolved with the discontinuation of valproic acid and L-carnitine administration. We discuss this case and review the possible mechanisms of valproic acid–associated encephalopathy and the efficacy of L-carnitine.

Valproic Acid Enhances iPSC Induction From Human Bone Marrow-Derived Cells Through the Suppression of Reprogramming-Induced Senescence.

Reprogramming of human somatic cells into pluripotent cells (iPSCs) by defined transcription factors is an extremely inefficient process. Treatment with the histone deacetylase inhibitor valproic acid (VPA) during reprogramming can improve the induction of iPSCs. To examine the specific mechanism underlying the role of VPA in reprogramming, we transfected human bone marrow-derived cells (HSC-J2 and HSC-L1) with lentiviruses carrying defined factors (OCT4, SOX2, KLF4, and c-MYC, OSKM) in the presence of VPA. We found that, OSKM lentiviruses caused significant senescence in transfected cells. Administration of VPA, however, significantly suppressed this reprogramming-induced stress. Notably, VPA treatment improved cell proliferation in the early stages of reprogramming, and this was related to the down-regulation of the activated p16/p21 pathway. In addition, VPA also released the G2/M phase blockade in lentivirus-transfected cells. This study demonstrates a new mechanistic role of the histone deacetylase inhibitor in enhancing the induction of pluripotency. J. Cell. Physiol. 231: 1719-1727, 2016. © 2015 Wiley Periodicals, Inc.

Abstract 17637: Combination Therapy With Hypothermic Target Temperature Management and Valproic Acid After Cardiac Arrest

Introduction: While hypothermic target temperature management (HTTM) has been regarded as a reliable strategy for post-cardiac arrest treatment, there are no pharmacologic agents proved to be neuroprotective against post-cardiac arrest brain injury. In recent years, many studies have shown that valproic acid (VPA), a well-known antiepileptic drug, is neuroprotective against various brain insults. VPA inhibits histone deacetylase activity and causes hyperacetylation of histones, followed by transcriptional activation of anti-apoptotic genes. In this study we tested the hypothesis that combination therapy of hypothermia and VPA could enhance neuroprotection and improve outcome. Methods: Male Long-Evans rats were instrumented for continuous telemetric EEG recording with video and then subjected to 8-minute asphyxia cardiac arrest. Nine rats that achieved the return of spontaneous circulation (ROSC) were allocated into the following 3 groups. Controlled normothermia (N group, 36.5-37.5 °C, n=3), HTTM (H group, 32-33 °C for 24 hours, n=3) and HTTM with VPA administration (HV group, 32-33 °C for 24 hours, 300 mg/kg, IV, n=3). Three-day survival, best achieved neurologic function score (NFS), the number of seizure event was compared between the 3 groups. Results: The 3-day survival was 33.3% in N group, 33.3 % in H group and 100 % in HV group (p=0.12). The best NFS averaged 263.33 ± 36.67 in N group, 380 ± 64.29 in H group and 468.33 ± 15.90 in HV group (p=0.13). The total number of seizure events in each group averaged 0.33 ± 0.33 in N group, 4.33 ± 2.96 in H group, 0 in HV group (p=0.20). Conclusions: These early results suggest that the combination of HTTM and VPA is a promising strategy that could result in synergistic neuroprotection after cardiac arrest.

Valproic Acid Limits Pancreatic Recovery after Pancreatitis by Inhibiting Histone Deacetylases and Preventing Acinar Redifferentiation Programs

The mechanisms by which drugs induce pancreatitis are unknown. A definite cause of pancreatitis is due to the antiepileptic drug valproic acid (VPA). On the basis of three crucial observations-that VPA inhibits histone deacetylases (HDACs), HDACs mediate pancreas development, and aspects of pancreas development are recapitulated during recovery of the pancreas after injury-we hypothesized that VPA does not cause injury on its own, but it predisposes patients to pancreatitis by inhibiting HDACs and provoking an imbalance in pancreatic recovery. In an experimental model of pancreatic injury, we found that VPA delayed recovery of the pancreas and reduced acinar cell proliferation. In addition, pancreatic expression of class I HDACs (which are the primary VPA targets) increased in the midphase of pancreatic recovery. VPA administration inhibited pancreatic HDAC activity and led to the persistence of acinar-to-ductal metaplastic complexes, with prolonged Sox9 expression and sustained β-catenin nuclear activation, findings that characterize a delay in regenerative reprogramming. These effects were not observed with valpromide, an analog of VPA that lacks HDAC inhibition. This is the first report, to our knowledge, that VPA shifts the balance toward pancreatic injury and pancreatitis through HDAC inhibition. The work also identifies a new paradigm for therapies that could exploit epigenetic reprogramming to enhance pancreatic recovery and disorders of pancreatic injury.

Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder

Valproic acid administration during gestational period causes behavior and biochemical deficits similar to those observed in humans with autism spectrum disorder. Although worldwide prevalence of autism spectrum disorder has been increased continuously, therapeutic agents to ameliorate the social impairment are very limited. The present study has been structured to investigate the therapeutic potential of melatonin receptor agonist, agomelatine in prenatal valproic acid (Pre-VPA) induced autism spectrum disorder in animals. Pre-VPA has produced reduction in social interaction (three chamber social behavior apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complex I, II, IV). Furthermore, Pre-VPA has increased locomotor activity (actophotometer), anxiety, brain oxidative stress (thiobarbituric acid reactive species, glutathione, and catalase), nitrosative stress (nitrite/nitrate), inflammation (brain and ileum myeloperoxidase activity), calcium levels and blood brain barrier leakage in animals. Treatment with agomelatine has significantly attenuated Pre-VPA induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, agomelatine also attenuated Pre-VPA induced increase in locomotion, anxiety, brain oxidative stress, nitrosative stress, inflammation, calcium levels and blood brain barrier leakage. It is concluded that, Pre-VPA has induced autism spectrum disorder, which was attenuated by agomelatine. Agomelatine has shown ameliorative effect on behavioral, neurochemical and blood brain barrier alteration in Pre-VPA exposed animals. Thus melatonin receptor agonists may provide beneficial therapeutic strategy for managing autism spectrum disorder.

Effects of Chard (Beta Vulgaris L. Var. Cicla) on Cardiac Damage in Valproic Acid-Induced Toxicity

The aim of this study was to examine the effects of chard on valproic acid (VPA)-induced cardiac damage. Female Sprague-Dawley rats were grouped as control, chard given control (100 mg/kg/day, by gavage), VPA (500 mg/kg/day, intraperitoneally) and chard given VPA (100 mg/kg/day chard by gavage, 500 mg/kg/day VPA, intraperitoneally). The aqueous extracts of chard leaves were given 1 h prior to administration of VPA for 7 days. Malondialdehyde (MDA), total sialic acid (SA) levels and catalase (CAT) activity significantly increased in the VPA group compared with the control group (P < 0.05). Chard administration significantly decreased MDA and SA levels in the control and in the VPA groups (P < 0.05). Chard administration also significantly increased CAT activities and glutathione levels both in the control and in the VPA groups (P < 0.05). As a conclusion, chard consumption may prevent cardiac tissue from oxidative stress and inflammation in VPA-induced toxicity. Practical Applications Valproic acid (VPA) is an antiepileptic drug and has severe toxic effects in experimental animals and humans. Chard (Beta vulgaris L. var. cicla) has antioxidant, antidiabetic, antitumor and hepatoprotective effects. Its protective effects against VPA toxicity have not been fully investigated yet. According to the results of this study, chard (B. vulgaris L. var. cicla) can be used as a dietary food supplement in the epilepsy treatment. The beneficial effect of chard consumption is an important finding in a nutritional point of view as chard contains many significant bioactive constituents for a healthy diet.

Valproic Acid Ameliorates Graft-versus-Host Disease by Downregulating Th1 and Th17 Cells.

Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation. Valproic acid (VPA) was described as a histone deacetylase inhibitor that had anti-inflammatory effects and reduced the production of proinflammatory cytokines in experimental autoimmune disease models. Using well-characterized mouse models of MHC-mismatched transplantation, we studied the effects of VPA on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of VPA significantly attenuated the clinical severity of GVHD, the histopathology of GVHD-involved organs, and the overall mortality from GVHD. VPA downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on GVHD was regulatory T cell independent. The effect of VPA was related to its ability to directly reduce the activity of Akt, an important regulator of T cell immune responses. Importantly, when mice received lethal doses of host-type acute leukemia cells, administration of VPA did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a unique role for VPA as a histone deacetylase inhibitor in reducing the donor CD4(+) T cells that contribute to GVHD, which may provide a strategy to reduce GVHD while preserving the GVL effect.

Fetal valproate syndrome as an experimental model of autism

High doses of valproic acid (VPA) can modify the activity of many genes by blocking histone deacetylases. Prenatal administration of VPA results in the development of fetal valproate syndrome in the offspring of laboratory animals. This syndrome is considered as a model of autism spectrum disorders. In this review, we discuss the characteristics of the brain state and activity during fetal valproate syndrome at different levels: from the molecular and cellular processes to the behavior. The characteristics of social interaction—the most relevant manifestations of autistic disorders—receive special attention. We present literature data and our own results.