Effect Of Sodium Valproate Research Articles

Facilitatory effect of Piperine on the Anticonvulsant effect of Sodium valproate against Pentylenetetrazole induced Seizures in mice

The present study was designed to find out the effect of piperine as an adjunctive therapy with sodium valproate against seizures induced by pentylenetetrazole (PTZ). Swiss albino mice (25-35g) received either vehicle, sodium valproate (300mg/kg), piperine (10mg/kg) or their combination orally for 8 days prior to PTZ (60mg/kg i.p.) administration. Sodium valproate significantly (P<0.05) increased the latency for clonic generalized seizures. Treatment with sodium valproate and piperine delayed the onset to both jerks (P<0.05) and clonic generalized seizures (P<0.001). All the animals in the combination group were protected from clonic generalized seizures. Our results suggest a favorable interaction of piperine with sodium valproate against PTZ induced seizures.

Sodium valproate ameliorates aluminum-induced oxidative stress and apoptosis of PC12 cells.

Objective(s):According to recent studies, valproate shows some protection against oxidative stress (OS) induced by neurotoxins. Current investigation tried to determine the possible ameliorating effects of sodium valproate (SV) against aluminum (Al)-induced cell death, apoptosis, mitochondrial membrane potential (MMP), and OS in PC12 cells.Materials and Methods:In this in vitro study, PC12 cells were treated with different concentrations of aluminum maltolate (Almal) with and without SV (50–400 µM). Cell viability was assessed by MTT assay. To measure quantitatively the effects of SV on Al-induced apoptosis and reactive oxygen species (ROS), flowcytometry using 7AAD/annexin-V and 2’, 7’-dichlorofluorescein diacetate staining were employed, respectively. MMP was monitored using the retention of rhodamine 123. Catalase (CAT) activity was assayed by the rate of decomposition of hydrogen peroxide. Results:Exposure of PC12 cells for 48 hr to Almal (125–2000 µM) significantly reduced cell viability (IC50=1090 μM), increased ROS generation and apoptosis, and reduced MMP and CAT activity. SV reduced the Almal-induced cell death and apoptosis. Furthermore, the effects of Almal on ROS generation, catalase activity, and MMP reduction were significantly diminished by SV. Conclusion:Data from this study suggest that SV can inhibit Al-induced cell death and apoptosis of PC12 cells via ameliorating OS.

Sodium Valproate Improves Skin Flap Survival via Gamma-Aminobutyric Acid and Histone Deacetylase Inhibitory System

Sodium valproate interacts with biological systems through different mechanisms such as activation of gamma-aminobutyric acid (GABA)-sensitive chloride channels and inhibition of histone deacetylase. In this study, we examined the effect of sodium valproate in random-pattern skin flap of rats and investigated its mechanisms of action. Different types of experiments were carried out. In acute treatment, different doses of sodium valproate (50, 100, 150, 300 mg/kg) were injected intraperitoneally 1 h before surgery. In chronic treatment, the substance was injected each day for 2 wk. The size of skin necrosis was measured 1 wk after the surgery. The rate of secondary healing, amount of weight gain, hair growth, and wound regeneration were measured 2 wk after operation. In acute treatment, sodium valproate (100 mg/kg) reduced significantly the length of skin necrosis (P < 0.05). Administration of bicuculline (competitive antagonist of GABAA, 20 mg/kg) increased the length of skin necrosis (P < 0.05). In addition, administration of 100 mg/kg of sodium valproate and subeffective dose of bicuculline (10 mg/kg) prevented the protective effect of sodium valproate on skin flap necrosis (P < 0.05). In the chronically treated skin flap group, 100 mg/kg of sodium valproate reduced the length of necrosis (P < 0.01). Weight gain in the valproate group was more than that in the control group (P < 0.05). Skin also healed faster in the sodium valproate group than in the control group (P < 0.001). Combination therapy of sodium valproate and trichostatin A (330 nmol/kg) reversed the effect of valproate (P < 0.05). This study demonstrate that sodium valproate accelerates skin secondary healing in a rat model of skin flap probably through a GABA and histone deacetylase–dependent mechanism.

P.122Feasibility open label trial shows no effect of sodium valproate for McArdle disease

P.122Feasibility open label trial shows no effect of sodium valproate for McArdle disease

Sodyum valproat kullanımına bağlı izole trombositopeni

Sodium valproate is one of the medications used in the treatment of schizoaffective disorder, bipolar disorder, and epilepsy. Tremor, drowsiness, Reye-like syndrome, hepatic failure, thrombocytopenia, pancreatitis are the most frequent side effects of this medication. Thrombocytopenia is another serious side effect of sodium valproate. Here, we report the case of a patient with thrombocytopenia associated with sodium valproate.

Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor‑3 (DR3) and decoy receptor‑3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride(Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma(OS) cell lines and human microvascular endothelial(HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF‑A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re‑expression of tumor suppressor genes in cancer cells, but also exert anti‑angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF‑A interference.

The effect of sodium valproate on differentiation of human adipose-derived stem cells into cardiomyocyte-like cells in two-dimensional culture and fibrin scaffold conditions.

Differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes is a complex phenomenon, and attempts to find an effective inducing agent are still ongoing. We studied the effect of fibrin scaffold and sodium valproate (VPA, as a histone deacetylase inhibitor) on the differentiation of human adipose-derived stem cells (hADSCs) into cardiomyocyte-like cells. The cells were cultured in culture flask (2D) and in fibrin scaffold (3D), fabricated of human plasma fibrinogen, with and without VPA (1mM). QRT-PCR, Western blot, and immunochemistry assays were used to evaluate the expression of cardiac markers at gene and protein levels. High levels of CD44, CD90, CD73, and CD105 were expressed on the surface of hADSCs. Treated encapsulated hADSCs (3D) presented significantly higher mRNA expression of HAND1 (1.54-fold), HAND2 (1.59-fold), cTnI (1.76-fold), MLC2v (1.4-fold), Cx43 (1.38-fold), βMHC (1.34-fold), GATA4 (1.48-fold), and NKX2.5 (1.66-fold) in comparison to 2D conditions at four weeks after induction. The protein expressions of NKX2.5 (0.78 vs 0.65), cTnI (1.04 vs 0.81), and Cx43 (1.11 vs 1.08) were observed in the differentiated cells both in 3D and 2D groups, while control cells were absolutely negative for these proteins. The frequency of cTnI and Cx43-positive cells was significantly higher in 3D (24.2 ± 15 and 12 ± 3%) than 2D conditions (19.8 ± 3 and 10 ± 2%). Overall, the results showed that VPA can increase cardiomyogenesis in hADSCs and that fibrin scaffold enhances the inductive effect of VPA. Results of this study may improve cell-based protocols for implementation of more successful cardiac repair strategies.

A comparative study of effect of sodium valproate &amp; flunarizine on psychomotor performance in patients of common migraine: A randomized, parallel, open label, prospective observational study

Introduction: Psychomotor performance results from the coordination of sensory and motor system through the integrative and organizational process of brain and central nervous system. Psychotropic drugs may adversely affect work performance which depends on psychomotor activities. Both valproate and flunarizine are widely used drugs in prophylaxis of migraine and they are known to have effect on psychomotor performance. Hence this study was carried out to evaluate the effect of valproate & flunarizine on psychomotor performance in patients of migraine with the help of battery of subjective & objective psychomotor tests over a period of 8 weeks. Materials and Methods: Patients were allocated to one of the two groups on first day of examination. Baseline psychomotor tests were measured using battery of tests including critical flicker fusion test (CFFT), hand steadiness test (HST), arithmetic ability test & reaction time monitoring. At the end of 4 weeks & 8 weeks, again tests using same methods employed previously were performed. Efficacy was calculated by using Migraine dairy template (0, 4, 8 weeks) & CGI Scale (end). A total of 44 patients were recruited with 22 patients in each arm. Results: Flunarizine (n=20) & valproate (n=20) significantly increased CFFT, AAT scores at the end of 8 weeks compared to baseline and significantly reduced HST, RT, Frequency, Duration and severity at the end of 8 weeks compared to baseline. When flunarizine was compared to valproate no statistical significance was found in scores of CFFT, AAT, HST, RT, Frequency, duration, severity, global improvement and efficacy index. Conclusion: Flunarizine & Valproate were found to be equally efficacious to improve psychomotor performance. Keywords: Sodium valproate, Flunarizine, Psychomotor, Migraine, Prophylaxis, Performance.

Valproic Acid Inhibits NA-K-2CL Cotransporter RNA Expression in Male But Not in Female Rat Thymocytes

Objective:The NKCC1 is a recognized tumorigenesis marker as it is important for tumor cell proliferation, differentiation, apoptosis, and tumor progression. The study aim was to investigate the effect of sodium valproate (VPA) on thymus NKCC1 RNA expression.Material and Methods:Wistar rats, age 4 to 5 weeks, were investigated in the control and VPA-treated male and female gonad-intact and castrated groups. The treatment duration with VPA 300 mg/kg/d was 4 weeks. Rat thymus was weighted; its lobe was taken for the expression of NKCC1 RNA determined by the real-time polymerase chain reaction method.Results:The RNA expression of the Slc12a2 gene was found to be significantly higher in the gonad-intact male control compared with the gonad-intact female control (P = .04). There was a gender-related VPA treatment effect on NKCC1 RNA expression in thymus: The Slc12a2 gene RNA expression level was found to be decreased in VPA-treated gonad-intact males (P = .015), and no significant VPA effects were found in the castrated males and in the gonad-intact and castrated females compared with the respective controls (P > .05).Conclusions:The study showed a gender-related difference in the NKCC1 RNA expression in rat thymus. The VPA decreases the NKCC1 expression in the thymus only in gonad-intact male rats. The NKCC1 RNA expression downregulation by VPA could be important for further VPA pharmacological studies in oncology.

Effects of Sodium Valproate, Levetiracetam and Phenytoin Therapy on Evoked Potentials in Children with Epilepsy

Effects of Sodium Valproate, Levetiracetam and Phenytoin Therapy on Evoked Potentials in Children with Epilepsy

The research for sodium valproate depress the expression of proliferating cell nuclear antigen and heparanase of hepatocellular carcinoma in nud mice via reversing low-level histone acetylation

Objective To explore the inhibitory effect of sodium valproate on human hepatoma cell line SMMC-772l xenograft in nud mice and the possible mechanisms. Methods The nude mice tumor model was established by subcutaneous injection of hepatic cancer cells in the right upper limb of the mice. When the tumor grew to (100-150) mm3, the mice were divided randomly into two groups and injected with VPA or DMSO respectively. The volume and weight of tumor were measured. Real-time PCR assay was used to detect the expression of proliferating cell nuclear antigen (PCNA) and heparanase (HPA) mRNA in tumor tissues of different groups. Western blotting assay and immunohistochemistry were used to detect the expression of PCNA and HPA protein in tumor tissues of different groups. Results The volume and weight of treatment group were significantly lower than the control group at the end of the experiment [(0.261±0.070) cm3 vs. (0.396±0.010) cm3, t=-42.321, P<0.05, (0.51±0.07) g vs. (0.83±0.14) g, t=-26.116, P<0.05]; RT-PCR results showed that compared with control group, the expression of PCNA and HPA mRNA in VPA-treated group was remarkably suppressed [(0.491±0.06) vs. (0.899±0.038), t=-112.316, P<0.05, (0.438±0.016) vs. (0.829±0.036), t=-127.768, P<0.05]; Western blotting assay and immunohistochemistry showed that the level of PCNA and HPA protein in VPA-treated group were lower remarkably than that in control group [(0.816±0.063) vs. (1.592±0.071), t=-17.561, P<0.05; (0.879±0.083) vs. (1.792±0.170), t=-17.140, P<0.05]. Conclusion The in vivo study showed that VPA may down regulate the expression of PCNA and HPA by reversing the low acetylation level of histone proteins, so as to inhibit the proliferation and decrease the ability of invasion and metastasis of hepatocellular carcinoma cells. Key words: Sodium valproate; Histone acetylation; Hepatocellular carcinoma; Proliferating cell nuclear antigen; Heparanase

Sodium valproate suppresses abnormal neurogenesis induced by convulsive status epilepticus.

Status epilepticus has been shown to activate the proliferation of neural stem cells in the hippocampus of the brain, while also causing a large amount of neuronal death, especially in the subgranular zone of the dentate gyrus and the subventricular zone. Simultaneously, proliferating stem cells tend to migrate to areas with obvious damage. Our previous studies have clearly confirmed the effect of sodium valproate on cognitive function in rats with convulsive status epilepticus. However, whether neurogenesis can play a role in the antiepileptic effect of sodium valproate remains unknown. A model of convulsive status epilepticus was established in Wistar rats by intraperitoneal injection of 3 mEq/kg lithium chloride, and intraperitoneal injection of pilocarpine 40 mg/kg after 18-20 hours. Sodium valproate (100, 200, 300, 400, 500, or 600 mg/kg) was intragastrically administered six times every day (4-hour intervals) for 5 days. To determine the best dosage, sodium valproate concentration was measured from the plasma. The effective concentration of sodium valproate in the plasma of the rats that received the 300-mg/kg intervention was 82.26 ± 11.23 μg/mL. Thus, 300 mg/kg was subsequently used as the intervention concentration of sodium valproate. The following changes were seen: Recording excitatory postsynaptic potentials in the CA1 region revealed high-frequency stimulation-induced long-term potentiation. Immunohistochemical staining for BrdU-positive cells in the brain revealed that sodium valproate intervention markedly increased the success rate and the duration of induced long-term potentiation in rats with convulsive status epilepticus. The intervention also reduced the number of newborn neurons in the subgranular area of the hippocampus and subventricular zone and inhibited the migration of newborn neurons to the dentate gyrus. These results indicate that sodium valproate can effectively inhibit the abnormal proliferation and migration of neural stem cells and newborn neurons after convulsive status epilepticus, and improve learning and memory ability.

Curly Hair: A Rare Side Effect of Sodium Valproate in a Child

Curly Hair: A Rare Side Effect of Sodium Valproate in a Child

EFFECT OF SODIUM VALPROATE ON THE STRUCTURE OF THE RENAL CORTEX OF ADULT MALE ALBINO RAT AND THE ROLE OF CINNAMON

Background: Valproic Acid (VPA) is one of the most widely prescribed antiepileptic drugs and is regarded as a first choice for most forms of seizures. Although valproic acid has a wide therapeutic window, yet it is associated with many adverse effects. Objectives: Evaluation of the effect of sodium valproate on renal cortex structure of adult male albino rats, and the role of cinnamon. Materials and Methods: Twenty four adult male albino rats weighing 160-180 grams were divided into four equal groups: Group I: control group, group II: sodium valproate group (500 ml/kg/day orally), group III: Cinnamon extract group (4ml/rat/day orally) and group IV: sodium valproate and cinnamon extract group. Drugs were given orally once daily for four weeks. Kidney samples were collected for histological, imunohistochmical and ultrastructural studies. Blood urea nitrogen (BUN) and serum creatinine (sCr) concentration were measured. Morphometric quantitative study for area percentage of collagen fibers and Caspase-3 +ve cells were done. Results: Examination of the renal cortex of sodium valproate ingested group demonstrated atrophied glomerulus with collapsed tuft, widening of bowman's space, degenerated tubule, hemorrhage and cellular infiltration. Moreover, the collagen fibers increased as well as focal loss of the basement membrane and brush border of the tubules. Caspase-3 +ve cells significantly increased after sodium valproate administration. Rarefaction of the cytoplasm, degeneration of mitochondria, loss of apical microvilli and pyknotic nucleus were observed in the electron microscopically study. The kidney functions demonstrated significant increase in concentration of blood urea nitrogen (BUN) and serum creatinine (sCr). In contrast, cinnamon extract administration with sodium valproate ingested group showed some amelioration in the renal cortex structure and function. Conclusion: Sodium valproate aggravated the histological structure of the renal cortex. However, cinnamon extract could ameliorate the changes due to its antioxidants effect.

Sodium valprovate suppresses autophagy in SH-SY5Y cells via activating miR-34c-5p/ATG4B signaling pathway

To investigate the effect of sodium valproate (VPA) on activation of miR-34c-5p/ATG4B signaling pathway and autophagy in SH-SY5Y cells. Routinely cultured SH-SY5Y cells were treated with VPA at different doses for 24 h, and the changes in the mRNA levels of ATG4B and miR-34c-5p and the protein expression of ATG4B were assessed using qRTPCR and immunoblotting, respectively. The effect of transfection with a plasmid containing ATG4B promoter on the promoter activity of ATG4B in VPA-treated SH-SY5Y cells was assessed using the reporter gene assay. The stability of ATG4B mRNA was analyzed with qPCR in SH-SY5Y cells treated with VPA alone or with VPA combined with the transcription inhibitor actinomycin D. The expression level of miR-34c-5p was detected using qPCR in SH-SY5Y cells treated with VPA alone or with VPA combined with miR-34c-5p mimics or antagonist, and the role of miR-34c-5p in VPA-induced ATG4B down-regulation was evaluated. The changes in the level of autophagy were evaluated by detecting LC3-Ⅱ expression in the cells after treatment with VPA or VPA combined with miR-34c-5p antagonist. VPA dose-dependently down-regulated the expression of ATG4B at both the mRNA and protein levels in SH-SY5Y cells. VPA treatment did not significantly affect the promoter activity of ATG4B, but obviously lowered the mRNA stability of ATG4B in SH-SY5Y cells. VPA treatment up-regulated the expression of miR-34c-5p, and the miR-34c-5p antagonist reversed VPA-induced down-regulation of ATG4B in SH-SY5Y cells. VPA also down-regulated the expression level of LC3-Ⅱ in SH-SY5Y cells. VPA suppresses autophagy in SH-SY5Y cells possibly via activating miR-34c-5p/ATG4B signaling pathway.

Serotonergic mechanisms in the 6-Hz psychomotor seizures in mice

Serotonin (5-hydroxytrytamine (5-HT)) plays an important role in experimental seizures. Recently, we reported the depletion of 5-HT by parachlorophynylalanine (PCPA) in whole brain to enhance 6-Hz psychomotor seizures in mice. In the present work, we investigated the effect of 5-HT depletion in cortex and hippocampus, brain regions relevant for epilepsy, on behavioral and ultra-structural changes following 6-Hz psychomotor seizures in mice. In addition, we studied the effect of sodium valproate (SVP) on behavioral, biochemical, and ultra-structural effects induced by 6 Hz. Behavioral changes induced by 6 Hz stimulation were characterized as the increased duration of Straub's tail, stun position, twitching of vibrissae, forelimb clonus, and increased rearing and grooming. PCPA administration further enhanced while SVP reduced these behaviors in mice. The 6-Hz psychomotor seizure induced ultra-structural changes in both cortex and hippocampus in mice treated with PCPA. Furthermore, PCPA administrations followed by 6Hz-induced seizures were accompanied by reduced hippocampal and cortical 5-HT. SVP attenuated the PCPA-induced ultra-structural changes and alterations of 5-HT content in the mouse brain. The study suggests the involvement of 5-HT in the 6 Hz psychomotor seizures and in the mechanisms of action of SVP against such seizures in mice.

The Therapeutic Effects of Low-Frequency Electrical Stimulations Adjunct to Sodium Valproate on Seizure and Behaviors.

Introduction:Consuming antidepressant medications induce several problems leading to the need for alternative agents for emotional disturbances. Antidepressant medications increase the seizure risk; thus, alternative treatments, like Antiepileptic Drugs (AED), might be useful for patients with epilepsy comorbid with a psychiatric disorder. The present study evaluated the behavioral effects of sodium valproate, a none effective dose in seizure treatment [100 mg/kg; Intraperitoneal (IP)] along with the application of Low-Frequency Stimulations (LFS) during CA1 hippocampal kindling.Methods:In total, 42 male rats were randomly divided into 6 groups, including control group with intact animals handled daily (I); sham group which was subjected to the surgical process, but received no real stimulation (II); saline-kindled Kindled group (S.kindled) which were stimulated daily with the following protocol: 3 strain of 50Hz monophasic pulses of 1ms duration applied 12 times a day with the threshold intensity at intervals of 10 minutes where saline was administrated 15 min before kindling stimulations (III); saline-kindled-LFS group (K4LFS) in which saline was injected 15 min before kindling stimulations and LFS was applied daily after the termination of kindling stimulation (IV); drug-kindle group (Drug100.kindled) that underwent rapid kindling procedure daily where sodium valproate (100 mg/kg) was administrated 15 min before kindling stimulations(V), and drug-kindled-LFS (Drug100.kindled.4LFS) group in which drug and LFS were administrated respectively before and after kindling stimulations (VI). The behavioral tests were assessed using elevated plus maze, open field, and forced swim tests.Results:The combination of sodium valproate (100 mg/kg) and LFS significantly decreased cumulative seizure severity compared with the kindle group. Thus, it provided a strong seizure suppressing effect. Additionally, sodium valproate and LFS increased the percentage of Open Arms (OAs) entries and the OAs exploration; they also decreased jumping from elevated plus maze test and rearing in open field test. Furthermore, there was no significant change in the OAs entries and OAs exploration percentages, jumping from apparatus, and rearing in open field in Drug100. Kindled, K4LFS, and Drug100.kindled.LFS groups, compared with the sham group. There was no significant difference in the latency to first immobility and the duration of immobility in K4LFS groups compared with the S. kindled group. In the drug-kindled group, the latency to first immobility significantly increased, and the duration of immobility decreased, compared with the S. kindled group. Besides, the latency to first immobility significantly increased, and the duration of immobility decreased in drug-kindled-LFS, compared to S. kindled group; however, the latency to first immobility was not significantly changed, compared to drug-kindled groups.Conclusion:Sodium valproate and LFS can modulate the function of the brain regions involved in emotional processing in epilepsy, as well as anxiety- and depressive-like behaviors. Such a combination could also decrease emotional disturbances induced by the kindling process.

Sodium Valproate Ameliorates Neuronal Apoptosis in a Kainic Acid Model of Epilepsy via Enhancing PKC-Dependent GABAAR γ2 Serine 327 Phosphorylation.

GABA is a dominant inhibitory neurotransmitter in the brain and A type GABA receptor (GABAAR) phosphorylation is critical for GABA-mediated inhibitory effect. However, its role in the neuroprotective effect of sodium valproate (VPA), a prevalent drug for treating patients with epilepsy, remains elusive. The present study was conducted to explore the role of GABAAR phosphorylation in the neuroprotection of VPA against a kainic acid-induced epileptic rat model and the potential molecular mechanisms. Neuronal apoptosis was evaluated by TUNEL assay, PI/Annexin V double staining, caspase-3 activity detection and Bax and Bcl-2 proteins expression via Western blot analysis. The primary rat hippocampal neurons were cultivated and cell viability was measured by CCK8 detection following KA- or free Mg2+-induced neuronal impairment. Our results found that VPA treatment significantly reduced neuronal apoptosis in the KA-induced rat model (including reductions of TUNEL-positive cells, caspase-3 activity and Bax protein expression, and increase of Bcl-2 protein level). In the in vitro experiments, VPA at the concentration of 1mM for 24h also increased cell survival and suppressed cell apoptosis in KA- or no Mg2+-induced models via CCK8 assay and PI/Annexin V double staining, respectively. What is more important, the phosphorylation of γ2 subunit at serine 327 residue for GABAAR was found to be robustly enhanced both in the KA-induced epileptic rat model and neuronal cultures following KA exposure after VPA treatment, while no evident alteration was found in terms of GABAAR β3 phosphorylation (408 or 409 serine residue). Additionally, pharmacological inhibition of protein kinase C (PKC) clearly abrogated the neuroprotective potential of VPA against KA- or free Mg2+-associated neuronal injury, indicating a critical role of PKC in the effect of GABAAR γ2 serine 327 phosphorylation in VPA's protection. In summary, our work reveals that VPA mitigates neuronal apoptosis in KA-triggered epileptic seizures, at least, via augmenting PKC-dependent GABAAR γ2 phosphorylation at serine 327 residue.

SODIUM VALPROATE EFFECTS ON LIPID PROFILE AND GLUCOSE LEVEL IN NORMAL AND DIABETIC RABBITS

Background: Sodium valproate has turn out to be the most commonly prescribed antiepileptic drug (AED) worldwide. It is also prescribed to diabetic mellitus (DM) patient for treatment of neuropathic pain. Changes in lipid levels and lipid metabolism usually accompanied with diabetic disease leading to increases in circulating levels of free fatty acids (FFA), triglycerides and dense low-density lipoprotein together with reduced levels of high-density lipoprotein cholesterol levels. Objective: To investigate the effect of sodium valproate on lipid profile and glucose level and highlight these effects with and without diabetic disease. Methods: Thirty-two healthy, local domestic rabbits of both sexes were used in the present study. Animals were allocated into two main groups, group A and B. According to induction of diabetes both groups received the same food and put in the same environmental condition. blood glucose level and lipid profile has been done for all groups. Results: There was significant difference in the blood glucose level in the normoglycemic rabbits treated with sodium valproate (200 mg/kg) compared to the untreated (negative control group). The effect of valproate was also observed by the significant difference of blood glucose level in alloxan-induced diabetic rabbits treated with sodium valproate (200 mg) compared with the positive control group. Also, we have statistically observed the significant increase in total cholesterol (TC), low density lipoprotein – cholesterol (LDL-C), and triglyceride (TG) levels in normoglycemic rabbits treated with sodium valproate (200 mg/kg) compare to the negative control group, however, there is no significant difference regarding the high-density lipoprotein – cholesterol (HDL-C) level. As for the alloxan-induced diabetic rabbits, there was a statistically significant difference observed indicated an increase in level of TC, LDL-C, and TG and a decrease in HDL-C. Conclusion: The effect of sodium valproate on glucose level and lipid profile in diabetic rabbits could reflect a possible hypoglycemic and dyslipidemic effects which could be dangerous if the patient is on anti- diabetic drugs with or without cardiovascular accident, although it may be dose-dependent and still falls in the hypothesis field but further experimental studies on human are needed to explore this theory. Keywords: Sodium valproate, anticonvulsants, glucose, lipid Citation: Abdul Bari MA. Sodium valproate effects on lipid profile and glucose level in normal and diabetic rabbits. Iraqi JMS. 2018; 16(3): 247-257. doi: 10.22578/IJMS.16.3.4

Гипобарическая эпилептиформная реакция у крыс линии Крушинского-Молодкиной как новая экспериментальная модель для тестирования антиконвульсантов

Ранее было установлено, что в ответ на резкое снижение атмосферного давления у крыс линии Крушинского-Молодкиной (КМ) возникает двигательное возбуждение, переходящее в клонико-тонический судорожный припадок - гипобарическая эпилептиформная реакция (ГЭР). Цель исследования. Подтвердить пригодность ГЭР у крыс линии КМ для тестирования антиконвульсантов. Методика. Для моделирования ГЭР крыс помещали в индивидуальную проточную барокамеру, снабженную высотомером, и «поднимали» с помощью вакуум-насоса до «высоты» 5000 метров со скоростью 50 м/с (декомпрессия). В процессе «подъема» у крыс возникала ГЭР. Антиконвульсанты карбамазепин и вальпроат натрия вводили крысам внутрибрюшинно в дозе 30 мг/кг и 200 мг/кг соответственно. Параметры ГЭР оценивали до и после введения антиконвульсантов. Результаты. Показано, что через 1-1,5 часа после введения антиконвульсантов ГЭР наблюдалась лишь у 30% и 40% крыс, при этом «высота» (в метрах) начала двигательного возбуждения увеличивалась и снижалась тяжесть припадка в баллах. У остальных крыс наблюдалось полное отсутствие ГЭР. Протекторный эффект карбамазепина исчезал через 24 часа после его инъекции, тогда как протекторный эффект вальпроата натрия через 24 часа сохранялся у 50% крыс. Заключение. На модели рефлекторной эпилепсии, вызываемой вакуум декомпрессией, установлено, что карбамазепин и вальпроат натрия одинаково эффективны через 1-1,5 часа после их введения, однако вальпроат натрия оказывал более пролонгированный протекторный эффект по сравнению с карбамазепином. ГЭР у крыс КМ может быть использована в качестве экспериментальной модели для тестирования антиконвульсантов. Previously it was found that Krushinsky-Molodkina (KM) rats responded to a sharp decline in atmospheric pressure with a hypobaric epileptiform reaction (HER), motor excitation resulting in tonic-clonic seizure. The aim of the study was to confirm that HER was suitable for testing anticonvulsants in KM rats. Methods. Carbamazepine and sodium valproate were administered to rats intraperitoneally at doses of 30 mg/kg and 200 mg/kg, respectively. For modeling HER, rats were placed in an individual chamber equipped with an altimeter and “elevated” to a simulated altitude of 5,000 m at a speed of 50 m/sec using a vacuum pump. In the process of elevation, rats developed HER. The HER parameters were evaluated before and after the anticonvulsant administration. Results. In 1-1.5 hours after administration of the anticonvulsants, carbamazepine and sodium valproate, HER was observed only in 30% and 40% of rats. Furthermore, the “altitude” in meters of the motor excitation onset was increased whereas the seizure severity in scores was decreased. The rest of the rats had no signs of HER. The protective effect of carbamazepine disappeared at 24 hours after the injection while the protective effect of sodium valproate remained in 50% of rats. Conclusion. Using a model of reflex epilepsy induced by vacuum decompression, carbamazepine and sodium valproate were shown to be equally effective in 1-1.5 hours after their administration; however, the protective effect of sodium valproate stayed longer than that of carbamazepine. HER in KM rats can be used as an experimental model for testing anticonvulsants.