valproic acid

Thymoquinone (TQ) is the main bioactive component of Nigella sativa L. and has anti-oxidant, anti-hepatotoxic, anti-cancer, anti-hypertensive, hypoglycemic, anti-inflammatory, and lipid-lowering properties. In this study, we investigated the protective properties of TQ on the cytochrome P450 enzyme system, peroxisome proliferator-activated receptors, and gene expressions involved in apoptosis, which are disrupted by valproic acid (VPA). 

The rats were put into control, VPA, and VPA+TQ groups. The weight of the body and liver were recorded. Liver tissue samples were evaluated for gene expressions (Bcl-2, p53, CYP2B1, CYP2B2, PPARα, and PPARγ), histopatology, and immunohistochemistry (CAS-3 and NOX-4). Additionally, serum was used to measure liver function parameters (ALT, AST, LDH, LDL, and HDL). 

The VPA+TQ group had significantly lower expression of p53 (P<0.05), CYP2B1 (P<0.05), CYP2B2 (P<0.05), PPARα (P<0.05), and PPARγ (P<0.05) genes compared to the VPA groups, while Bcl-2 (P<0.05) gene expression increased. TQ decreased CAS-3 and NOX-4 levels. Also, TQ reduced ALT (P<0.05), AST (P<0.05), LDL (P<0.01), total bilirubin (P<0.05), and LDH (P<0.05) enzyme activity while increasing HDL (P<0.0001). TQ treatment improved fresh liver weight considerably (P<0.0001). 

TQ substantially protects liver tissue by modifying gene expression, lowering oxidative stress, and increasing liver function. It significantly counteracts VPA’s toxic effects, demonstrating its promise as a hepatoprotective agent in avoiding liver damage.

Natural compounds, such as Oleuropein, Quercetin, Coumarin, and Valproic acid, play a vital role in preventing the spread and progression of cancer. Oleuropein increases the expression of certain caspases, Quercetin reduces the activity of the PI3K/Akt/IKK-/NF-κB pathway, Coumarin inhibits aromatase, and Valproic acid acts as an inhibitor of histone deacetylases. This study aimed to produce a quadruple magnetic nanocomplex with high bioavailability and to examine whether this nanocomplex can induce apoptosis in MCF7 breast cancer cell lines.

A silicon bridge (Sio-N-) was built using nanomagnetic iron and methoxysilane to create a magnetic nanocomplex that incorporated the four natural substances. This quadruple nanocomplex was then analyzed using various spectroscopic techniques and measurements. The researchers assessed the inhibitory impact of the nanocomplex on apoptotic genes in the MCF7 breast cancer cell line using the MTT assay, Hoechst staining, flow cytometry, and real-time PCR analysis.

The magnetic nanocomplex exhibited a greater level of toxicity and reduced the number of cancer cells compared to any of the individual natural compounds or the quadruple combination without nanoparticles. The quadruple magnetic nanocomplex induced overexpression of the pro-apoptotic genes P53, Bim, and Bak, while reducing the expression of the anti-apoptotic gene Bcl2. Additionally, the nanocomplex treatment increased the expression level of genes involved in apoptosis by up to two-fold.

The combination of plant-derived natural compounds and magnetic nanoparticles can enhance the toxicity and concentration of the materials against breast cancer cells. This approach may provide synergistic effects through the modulation of various molecular pathways, leading to the inhibition of cancer cell proliferation and the induction of apoptosis.

Autism spectrum disorder (ASD) is characterized by behavioral dysfunctions, including repetitive behaviors and impaired social interactions. Previous research has identified working memory deficits in individuals with ASD, often associated with prefrontal cortex abnormalities. Valproic acid (VPA), a well-known antiepileptic drug, has been linked to negative effects on brain development and an increased risk of ASD. This study explored the potential therapeutic impact of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) in mitigating oxidative stress and preserving neural structures in the context of ASD induced by prenatal exposure to VPA. Our investigation examined the role of LF-rTMS, a non-invasive brain stimulation technique, in modulating working memory (Y-maze), oxidative stress, and protecting neural structures. Oxidative stress, measured by malondialdehyde (MDA) in the prefrontal cortex, serves as a critical marker for evaluating cellular damage. Dendritic spine density was assessed using the Golgi impregnation method as a marker for neural structure protection. Our data indicated that LF-rTMS treatment significantly improves working memory function, reduces MDA level, and increases dendritic spine density in the prefrontal cortex. In conclusion, our findings suggest that LF-rTMS holds promise as a neuroprotective intervention, showing potential in reducing oxidative stress and preserving neural structures in a VPA-induced ASD model.

This experiment was carried out to investigate the protective effects of curcumin (CUR) on testicular damage induced by the valproic acid (VPA) administration. 

Male Wistar–Albino rats (n=28, 250–300 g) were randomly divided into four groups: Control (1 ml saline, oral), VPA (500 mg/kg, IP), CUR (200 mg/kg, oral), or VPA+CUR (500 mg/kg, VPA, IP plus 200 mg/kg CUR, oral). The treatments were applied for 14 days. Serum testosterone and testis [Janus kinases1 (JAK1), signal transducers and activators of transcription–3 (STAT–3), interleukin–6 (IL–6), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF–α), interleukin–18 (IL–18), and nuclear factor (NF)–κB)] samples were collected for biochemical analyses. Semen samples were subjected to microscopy for spermatological parameters. Testis tissue was also analyzed for histopathological and immunohistochemical methods. 

The VPA administration caused a 37% decrease in serum testosterone concentration and 5.32, 9.51, 2.44, and 3.68–fold increases in testicular tissue JAK1, STAT–3, IL–6, and MDA levels, respectively. There were also 50, 52, and 72% reductions in sperm motility, sperm viability, and the mean testicular biopsy score, respectively, accompanied by considerable degenerative changes and necrosis in seminiferous tubules in the VPA group. There is also an immune-positive reaction for IL–18 and NF–κB in only Leydig cells. 

The CUR treatment may be beneficial in restoring testicular damage through antiinflammatory and anti-oxidant potential.

Valproic acid (VPA) is a commonly used drug for treating epilepsy and other neurological and psychiatric disorders. Drug-induced liver injury (DILI) caused by VPA has been reported in several studies. MicroRNAs (miRNAs) are recognized as potent regulators involved in many biological processes and are currently considered promising biomarkers for detecting DILI. The aim of the present study was to evaluate the expression levels of two hepato-specific microRNAs, miR-122 and miR-155, in hepatocytes exposed to VPA. This study was conducted using HepG2 cell lines treated with different concentrations of VPA for 24, 48, 72, 96, and 120 hours. The results showed that exposure to VPA significantly elevated the transcription levels of both tested miRNAs in HepG2 cell lines after 24 hours. However, prolonged exposure down-regulated the expression levels of these miRNAs, possibly due to VPA-induced cell death. We suggest that the significant decrease in miRNA expression in treated cells is correlated with VPA-induced apoptosis, followed by enhanced cell death after 120 hours of VPA exposure. Our findings imply that miR-122 and miR-155 play an important role in valproic acid detoxification and have prognostic or therapeutic implications.

Opioids can lead to mood disorders, anxiety, depression, and cognitive impairment. Valproic acid (VPA) has neuroprotective effects that can prevent neural degeneration. This study aims to examine the impact of VPA on learning, social interaction, and depression in mice dependent on morphine.

Subjects were divided into four groups and received injections of saline, VPA, morphine, or a combination of VPA and morphine for eight days. Behavioral tests were conducted on day 8, and then administration of VPA and morphine was stopped, leading to spontaneous withdrawal syndrome. Behavioral tests were repeated on day 11, and histological analysis was performed on the hippocampus.

The preference index (PI%) decreased in the novel object recognition test in the VPA and morphine sulfate (MOR) groups compared to the control (CTL) group in the chronic phase. The concomitant administration of VPA and morphine caused an increase in social interaction criteria in both the chronic and withdrawal phases. The decrease in immobility time in the VPA and MOR + VPA groups compared to the CTL group in the withdrawal phase was not statistically significant in the tail suspension test (TST). In Nissl staining, the combination of MOR + VPA led to a significant decrease in the DC/All cell ratio compared to the individual MOR and VPA groups (P < 0.05).

VPA may improve social relationships and depression indices during morphine withdrawal. VPA may potentially mitigate the cellular changes in the CA1 of the hippocampus induced by morphine.

Valproic acid (VPA) is a well-known antiepileptic drug; however, it has adverse effects on different body organs, particularly as a result of inducing oxidative stress in the liver. Taurine (Tau) is an amino acid prevalent in the brain that possesses anti-tumor, anti-toxic, and antioxidant properties. This study aimed to investigate the potential of the co-treatment of Tau in mitigating the deleterious effects of VPA in pentylenetetrazole (PTZ) epileptic rats.

A total of 42 rats were divided into six groups of seven as follows: control group, PTZ-treated group (single dose, 60 mg/kg intraperitoneally [IP]), VPA-treated group (500 mg/kg IP for 14 days), Tau-treated group (100 mg/kg orally for 28 days), VPA+PTZ group, and Tau+VPA+PTZ group. The liver function, antioxidant status, and lipid profile markers were evaluated spectrophotometrically.

The IP injection of PTZ and VPA elevated aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyltransferase levels. These treatments caused negative alterations in protein concentrations, antioxidant status, and lipid profile markers of the rats’ sera. The treatment with Tau+VPA, on the other hand, improved liver function, restored fairly normal total protein and albumin levels, and improved malondialdehyde, glutathione peroxidase, and total antioxidant capacity concentrations. Furthermore, the Tau+VPA treatment significantly controlled total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein levels, compared to the VPA+PTZ treatment.

The treatment with Tau+VPA is highly effective in controlling the unfavorable side effects of VPA in an epileptic rat model.

Valproic acid (VPA) is the most widely used chemical to develop the preclinical model of autism spectrum disorder (ASD). However, in addition to inducing autism, it causes different teratogenic effects like teeth malformation, tail kink, and abnormal body growth in offspring. So far, no study has explored VPA-induced maternal misbehavior, miscarriage, and maternal cannibalism. We aimed to determine the cannibalistic effects of VPA in pregnant female Wistar rats and VPA’s influence on causing miscarriage frequency.

Our study was conducted on pregnant Wistar rats. On gestation day (GD) 12.5, they were treated with VPA (600 mg/kg intraperitoneal) dissolved in saline at 250 mg/mL concentration. The observations were mean litter size, mean male/female pups, mean mortality, maternal cannibalism, mean number of pups alive, cannibalism of malformed pups, miscarriage, survival analysis of pups, and odds and risk ratio were calculated for deaths observed in both study (control and VPA-treated) groups. The study was conducted till the weaning period. 

VPA-exposed pregnant females portrayed significantly decreased litter size (P<0.0001), significantly higher cannibalistic behavior (P=0.0023), and significantly higher cannibalism of malformed pups (P=0.0484) than the control group. VPA had caused complete pregnancy loss (miscarriage) in 5 pregnant females. Moreover, the VPA group’s mortality percentage (P=0.0019) was significantly higher than the control group.

Overall, VPA has marked teratogenic effects (anatomical and morphological changes in offspring) with maternal behavior disruption, which causes cannibalism in Wistar female rats. The current manuscript findings can aid in investigating the novel mechanisms involved in maternal behavior disruption during the development of the VPA autism model.

Due to the crucial role of polyamines during fetal growth and development, we aimed to determine the effect of prenatal administration of agmatine, an endogenous active metabolite of arginine, and a nutritional supplement, on autistic-like behaviors, oxidative-anti-oxidative profile, and histopathological changes of the prefrontal cortex (PFC) and CA1 area of the hippocampus in valproic acid (VPA) model of autism in male rats.  VPA was injected intraperitoneally on embryonic days (ED) 12.5, and the pregnant rats were gavaged with agmatine between E6.5 to E18.5 (13 days), at doses of 0.001, 0.01, and 0.1 mg/kg. The autism-like behaviors and memory of male pups were analyzed via open-field, three-chamber, and novel object recognition tests. Serum oxidative stress and the histological changes in the PFC and CA1 were assessed at the end of the study.  The results suggest that prenatal agmatine reduced autistic-like behaviors by decreasing cell loss in CA1 and PFC. We observed no alterations in superoxide dismutase (SOD) level and total anti-oxidant capacity (TAC) between groups. VPA decreased catalase (CAT) activities, while agmatine decreased malondialdehyde (MDA) activity.  Overall, this investigation suggests that agmatine may be a potential candidate for the early treatment and even prevention of appearance of autism symptoms.

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.

Due to the lack of early diagnosis, it is unclear how the environmental stimulations in infancy would affect the underlying structures of Autism Spectrum Disorder (ASD), as well as the onset or severity of symptoms. The study aimed to investigate the effects of receiving pre-weaning environmental enrichment on the severity of ASD symptoms and the hippocampal level of brain-derived neurotrophic factor (BDNF) in the valproic acid (VPA) rat model.

Male rats exposed to valproic acid (VPA) or normal saline (Sal) embryonally (E12.5) were randomly assigned to 4 environments: Standard (ST), pre-weaning environmental enrichment (PEE), secondary environmental enrichment (SEE) and PEE+SEE (EE). Behavioral tests were repeated at postnatal day (PND)30 and PND60, in the light phase with a blinded examiner. The BNDF level was determined at PND68.

In VPA rats, receiving PEE, increased social interactions and decreased anxiety, pain sensitivity even in early adulthood. Also, it reduced repetitive behavior but with no significant differences. The BDNF level in VPA-PEE and VPA-SEE was lower than VPA-ST, VPA-EE and saline groups. The biggest improvement in symptom severity was seen in EE.

Reduction of symptoms severity in VPA-PEE and the best performance in VPA-EE showed that rich and sensory overflew environment in infancy can change the formation of ASD. Finding might point to hyperactivity or a lack of regulation of BDNF levels in ASD. PEE most likely reduced hyperactivity, and continued environmental enrichment in EE, regulated the level of BDNF in the hippocampus.

Sodium valproate is recommended as a first-line drug to prevent migraine attacks, and sodae is an herbal medicine.

Sodium valproate and herbal sodae were compared for effectiveness and side effects.

A two-center, randomized, double-blind clinical trial included migraine patients from Kermanshah and Hamadan cities into two groups: Sodae herbal recipients and valproate (200 mg) recipients, for 3 months. A numerical rating scale (NRS) scale was used to measure residual pain at the end of each month of treatment. Also, a researcher-made form and the headache impact test (HIT-6) questionnaire were used. Side effects reported by the patients were collected, and liver function tests and complete blood cell count tests were conducted.

A total of 70 migraine patients were evaluated: 33 patients (47%) in the soda group and 37 patients (53%) in the valproate group. The NRS scores in both groups decreased constantly, with no significant difference (P=0.303). Also, HIT-6 scores were constantly reduced in both groups with no significant difference (P>0.05). More side effects are significantly (P=0.043) reported in the valproate group (54.05%) than in the sodae group (30.30%). The most common side effect in the valproate group was drowsiness (13.5%), while among the sodae group, it was diarrhea (15.1%).

The sodae and valproate did not differ in headache improvement, HIT-6 scores, and changes in laboratory parameters. However, the valproate group reported more side effects than the sodae group. Sodae is a suitable herbal medicine for preventing and controlling migraine attacks.

Valproic acid (VPA), which is often used to treat epilepsy, causes a variety of neurobehavioral impairments that closely resemble the phenotype of autism spectrum disorder (ASD) in prenatally exposed individuals. Although the neurobehavioral effects of extremely low concentrations of VPA have received limited research attention, several investigations have shown that the impact of VPA is connected with the concentration and exposure length.

In the current study, the aim was to find the lowest dose of VPA with the fewest side effects to induce behavioral phenotypes related to ASD in zebrafish.

Zebrafish embryos were first exposed to various concentrations of VPA (i.e., 1, 5, 15, 25, 48, and 75 µM) for 120 hours. Then, 42 days after conception, the survival rate, quality of hatching, and presence of deformity were assessed. Afterward, a 1 µM VPA was chosen based on observations, and behavioral experiments were carried out at 7, 21, and 42 days after fertilization (dpf). Additionally, 7dpf gene expression analysis was evaluated.

According to the obtained findings, behavioral abnormalities resembling ASD were induced in 7 and 21 dpf but not in 42 dpf after 120 hours of exposure to 1µM VPA. Real-time analysis in 7 dpf revealed significant changes in a number of genes linked to ASD, including lrp6, gsk3beta, chd8, and ctnnb.

In conclusion, 120 hours of exposure of zebrafish embryos to 1 µM of VPA might produce suitable VPA induces autism-like behavior models in zebrafish larvae to research early and long-term neurobehavioral and gene expression alterations. Studies on drug development might adopt this approach

Migraine is a common disorder in children that its prophylaxis with minimal side effects is momentous. This study aimed to compare the efficacy of Pregabalin and Sodium valproate in preventing migraine attacks.

Sixty-four children (aged 6-18) with migraines were recruited, as defined by Internation Headache Criteria (ICHD-III). They were randomly assigned to two groups: Sodium Valproate (n=32) and Pregabalin (n=32). The minimum dosage of drugs was prescribed in both groups. The patients were followed for four months. The parameters such as frequency, intensity, duration of migraine attacks, and the number of painkillers that the patients used monthly were recorded. The Spence Children’s anxiety scale was also used to evaluate medications’ effect on patients’ anxiety levels.

Two medications were equally effective in reducing the intensity and duration of attacks. Additionally, their effect on reducing the anxiety level of patients was equal. There was a significant difference between the effect of drugs on the frequency of migraine attacks at the end of the first and fourth months and the number of painkillers used at the end of the fourth month. The frequency of attacks was decreased by more than 50% in twenty-eight patients (90%) of Pregabalin recipients and twenty-one patients (84%) of Sodium Valproate recipients.

considering the better effect of Pregabalin in the reduction of frequency of migraine attacks and pain-reducing medications consumption, Pregabalin could be a proper substitute to Sodium valproate for migraine prophylactic treatment in children.

In this study, we aimed to investigate the combined effect of sodium valproate (SV) and lithium (Li) against viability, migration, and invasion of prostate cancer cell line. In this in vitro study, PC3 cells were treated with different concentrations of SV (2.5, 5.0, and 10 μM) and Li (2.5, 5.0, and 10 mM) either alone or in combination. Using the MTT test and annexin V/7ADD flow-cytometry, cell viability and apoptosis were assessed. Transwell chamber test was used to assess PC3 cells' invasion and migration. SV and Li alone had no significant effects on PC3 cell viability. However, the combination of SV and Li in all tested concentrations decreased the viability of PC3 cells in a dose dependent manner (P < 0.001). The combination of SV and Li (5.0 μM + 5.0 mM) increased apoptosis of PC3 cells compared with the control group (P = 0.003). Transwell assay showed that combination of SV with Li (5.0 μM + 5.0 mM) reduced the migration and invasion of PC3 cells significantly. The lack of a significant difference between the predicted and observed fractional inhibition for the effects of SV+Li suggests that SV and Li may have additive effects on lowering PC3 cell viability and invasiveness. These findings show that combined low doses of SV and Li could decrease the viability and invasiveness of the PC3 cells; therefore, it can be considered as a new strategy for the treatment of prostate cancer. However, further in vivo studies are required to confirm the results of this study.