Black radish root extract alleviates sodium valproate-induced liver damage via inhibiting mitochondrial membrane potential collapse and oxidative stress in mice

Objective:To explore the effect of black radish(Raphanus sativus L.var niger)root extract on liver enzymes,oxidative stress,and histopathological alterations in mice with sodium valproate-induced hepatotoxicity.Methods:Thirty-two mice were divided into four groups:the control group received drinking water by gavage,the second group was administered with 100 mg/kg of sodium valproate,the third group received 300 mg/kg of black radish root extract,and the fourth group was given both sodium valproate(100 mg/kg)and black radish root extract(300 mg/kg).After 28 days,the mice were euthanized,and serum levels of aspartate aminotransferase(AST),alanine aminotransferase(ALT),and alkaline phosphatase(ALP),along with liver malondialdehyde(MDA),reactive oxygen species(ROS),mitochondrial parameters,tumor necrosis factor-alpha(TNF-α)gene expression,and histopathological changes were assessed.Results:Sodium valproate caused hepatic damage in mice,characterized by elevated serum levels of liver enzymes,increased MDA and ROS levels and TNF-αgene expression,as well as histopathological alterations.The black radish root extract significantly alleviated sodium valproate-caused hepatic injury by decreasing the serum levels of ALT and AST,MDA,ROS,TNF-αgene expression,as well as mitochondrial impairment,but did not have a significant effect on sodium valproate-induced histopathological changes.Conclusions:The black radish root extract demonstrates protective effects against sodium valproate-induced liver injury,possibly through mitigating oxidative stress,mitochondrial impairment,and inflammatory mediator expression.

Acute liver failure with thrombotic microangiopathy due to sodium valproate toxicity:A case report

BACKGROUND Sodium valproate is widely used in the treatment of epilepsy in clinical practice.Most adverse reactions to sodium valproate are mild and reversible,while serious idiosyncratic side effects are becoming apparent,particularly hepatotoxicity.Herein,we report a case of fatal acute liver failure(ALF)with thrombotic microangiopathy(TMA)caused by treatment with sodium valproate in a patient following surgery for meningioma.CASE SUMMARY A 42-year-old man who received antiepileptic treatment with sodium valproate after surgery for meningioma exhibited extreme fatigue,severe jaundice accompanied by oliguria,soy sauce-colored urine,and ecchymosis.His postoperative laboratory values indicated a rapid decreased platelet count and hemoglobin level,severe liver and kidney dysfunction,and disturbance of the coagulation system.He was diagnosed with drug-induced liver failure combined with TMA.After plasma exchange combined with hemoperfusion,pulse therapy with high-dose methylprednisolone,and blood transfusion,his liver function deteriorated,and finally,he died.CONCLUSION ALF with TMA is a rare and fatal adverse reaction of sodium valproate which needs to be highly valued.

Protective effect of sodium valproate on motor neurons in the spinal cord following sciatic nerve injury in rats

BACKGROUND: Sodium valproate (VPA) is used to be an effective anti-epileptic drug. VPA possesses the characteristics of penetrating rapidly through the blood-brain barrier (BBB) and increasing levels of Bcl-2 and growth cone-associated protein (GAP) 43 in spinal cord. OBJECTIVE: To observe the effect of VPA on Bcl-2 expression and motor neuronal apoptosis in spinal cord of rats following sciatic nerve transection. DESIGN: Randomized controlled experiment. SETTING: Department of Hand Surgery and Microsurgery, Wuhan Puai Hospital. MATERIALS: A total of 30 male healthy SD rats of clean grade and with the body mass of 180-220 g were provided by Experimental Animal Center of Medical College of Wuhan University. Sodium Valproate Tablets were purchases from Hengrui Pharmaceutical Factory, Jiangsu. METHODS: The experiment was performed in the Central Laboratory of Wuhan Puai Hospital and Medical College of Wuhan University from February to May 2006. Totally 30 rats were randomly divided into two groups: treatment group (n =15) and model group (n =15). Longitudinal incision along backside of right hind limbs of rats was made to expose sciatic nerves, which were sharply transected 1 cm distal to the inferior margin of piriform muscle after nerve liberation under operation microscope to establish sciatic nerve injury rat models. Sodium Valproate Tablets were pulverized and diluted into 50 g/L suspension with saline. On the day of operation, the rats in the treatment group received 6 mL/kg VPA suspension by gastric perfusion, once a day, whereas model group received 10 mL/kg saline by gastric perfusion, once a day. L4-6 spinal cords were obtained at days 1, 4, 7, 14 and 28 after operation, respectively. Terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique and immunohistochemical method (SP method) were used to detect absorbance (A) of neurons with positive Bcl-2 expression. Apoptotic rate of cells (number of apoptotic cells/total number of cells×100%) was calculated. MAIN OUTCOME MEASURES: A value of neurons with positive Bcl-2 expression and apoptotic rate in spinal cord of rats in the two groups. RESULTS: A total of 30 SD rats were involved in the result analysis. ①expression of positive Bcl-2 neurons: A value of positive Bcl-2 neurons were 0.71±0.02, 0.86±0.04, 1.02±0.06 at days 4, 7 and 14, respectively after operation in the treatment group, which were obviously higher than those in the model group (0.62±0.03, 0.71±0.05, 0.89±0.04, t = 3.10-4.50, P < 0.05). ②apoptotic result of motor neurons: Apoptotic rate of motor neurons in spinal cord was (6.91±0.89)% and (15.12±2.34)% at days 7 and 14 in the treatment group, which was significantly lower than those in the model group [(9.45±1.61)%, (19.35±0.92)%, t = 2.39, 3.03. P < 0.05]. CONCLUSION: VPA can increase expression of Bcl-2 in spinal cord and reduce neuronal apoptosis in rats following sciatic nerve injury, and has protective effect on motor neuron in spinal cord of rats.

Effects of sodium valproate combined with levetiracetam in treatment of children epilepsy and its influences on serum S-100βand high mobility group box-1

Objective:To explore the effects of sodium valproate combined with levetiracetam in the treatment of children epilepsy,and its influences on serum S-100βand high mobility group box-1(HMGB-1)in children with epilepsy.Methods:A total of 160 children who were diagnosed as epilepsy in Baogang Hospital of Inner Mongolia from July 2016 to October 2018 were selected as research objects.They were randomly divided into the study group(n=80)and the control group(n=80)by the random number table method,i.e.,they were treated with sodium valproate combined with levetiracetam and sodium valproate alone,respectively.After 16 weeks of treatment,the effective rates of epileptic seizure treatment and the improvement of epileptiform discharge were evaluated,and chi-square test was used for statistical comparison.The related indicators,including serum tumor necrosis factor-(TNF-α),hypersensitive C-reactive protein(hs-CRP),homocysteine(Hcy),haematocrit(HCT),erythrocyte sedimentation rate(ESR),serum S-100βand HMGB-1,were measured before and after treatment.Paired t-test was used for the comparison in the above indicators within a group before and after treatment;group t-test was used for the comparison between two groups.Chi-square test was used for the comparison in the rate of adverse reactions during treatment between two groups.The study was approved by Ethics Committee of Baogang Hospital(Approval No.:BG201606073),and all children’s guardians were required to sign informed consent forms for clinical study.There were no statistically significant differences between two groups in general clinical data(p>0.05),such as sex constituent ratio,age,the course of disease,the frequency of epileptic seizure per year before treatment,the incidence of epileptiform discharge before treatment and the constituent ratio of types of epileptic seizure,etc.Results:1)After treatment,the effective rates of epileptic seizure treatment and the improvement of epileptiform discharge in the study group were 92.5%(74/80)and 85.0%(68/80)respectively,which were both significantly higher than those in the control group[68.8%(55/80)and 58.8%(47/80)],and the differences were statistically significant(Х^(2)=14.444,13.635;p<0.001).2)In the study group,the levels of serum TNF-α,hs-CRP and Hcy,as well as HCT and ESR after treatment were(53.1±14.0)pg/ml,(5.0±2.5)mg/L,(12.5±3.1)μmol/L,(38.1±5.1)%and(3.0±0.5)mm/h respectively,which were all significantly lower than those[(107.9±17.8)pg/ml,(10.1±2.5)mg/L,(42.2±5.8)μmol/L,(45.3±4.5)%and(5.2±0.6)mm/h]before treatment,and all the differences were statistically significant(t=21.644,12.902,40.393,9.468,25.194;p<0.001).In the control group,the levels of serum TNF-α,hs-CRP and Hcy,as well as HCT and ESR after treatment were(60.6±17.8)pg/ml,(8.2±2.2)mg/L,(15.2±3.1)μmol/L,(40.2±3.4)%and(4.5±0.6)mm/h respectively,which were all significantly lower than those[(112.4±14.3)pg/ml,(9.3±3.8)mg/L,(41.1±2.8)μmol/L,(44.6±5.5)%and(5.4±0.8)mm/h]before treatment,and all the differences were statistically significant(t=20.292,2.241,55.456,3.320,8.050;p<0.05).After treatment,the above indicators in the study group were all significantly lower than those in the control group,and all the differences were statistically significant(t=2.962,8.595,5.508,3.064,17.178;p<0.05).3)In the study group,the levels of serum S-100βand HMGB-1 after treatment were(0.65±0.38)μg/L and(5.3±2.4)μg/L respectively,which were significantly lower than those[(0.91±0.32)μg/L and(8.1±2.0)μg/L]before treatment,and the differences were statistically significant(t=4.681,8.020;p<0.001).In the control group,the levels of serum S-100βand HMGB-1 after treatment were(0.78±0.27)μg/L and(6.4±2.2)μg/L respectively,which were significantly lower than those[(0.88±0.25)μg/L and(7.9±1.7)μg/L]before treatment,and the differences were statistically significant(t=2.431,p=.016;t=4.826,p<0.001).After treatment,the levels of serum S-100βand HMGB-1 in the study group were significantly lower than those in the control group,and the differences were statistically significant(t=2.495,p=.014;t=2.840,p=.005).4)There was no significant difference between two groups in the rate of adverse reactions,such as nausea,vomiting,poor appetite,dizziness,drowsiness,hepatic and renal injury during treatment(p>0.05).Conclusions:The efficacy of sodium valproate combined with levetiracetam is obviously better than that of sodium valproate alone in the treatment of children epilepsy.The children patients’serum S-100βand HMGB-1 are more significantly reduced,resulting in a lower rate of adverse reactions,which has a certain clinical value.

Sodium valproate induces mitochondria-dependent apoptosis in human hepatoblastoma cells

Background Sodium valproate inhibits proliferation in neuroblastoma and glioma cells, and inhibits proliferation and induces apoptosis in hepatoblastoma cells. Information describing the molecular pathways of the antitumor effects of sodium valproate is limited; therefore, we explored the mechanisms of action of sodium valproate in the human hepatoblastoma cell line, HepG2.Methods The effects of sodium valproate on the proliferation of HepG2 cells were evaluated by the Walsh-sohema transform and colony formation assays. Sodium valproate-induced apoptosis in HepG2 cells was investigated with fluorescence microscopy to detect morphological changes; by flow cytometry to calculate DNA ploidy and apoptotic cell percentages; with Western blotting analyses to determine c-Jun N-terminal kinases （JNK）, p-JNK, Bcl-2, Bax, and caspase-3 and-9 protein expression levels; and using JC-1 fluorescence microscopy to detect the membrane potential of mitochondria. Statistical analyses were performed using one-way analysis of variance by SPSS 13.0 software.Results Our results indicated that sodium valproate treatment inhibited the proliferation of HepG2 cells in a dose-dependent manner. Sodium valproate induced apoptosis in HepG2 cells as it： caused morphologic changes associated with apoptosis, including condensed and fragmented chromatin; increased the percentage of hypodiploid cells in a dose-dependent manner; increased the percentage of annexin Ⅴ-positive/propidium iodide-negative cells from 9.52％ to 74.87％; decreased JNK and increased phosphate-JNK protein expression levels; reduced the membrane potential of mitochondria; decreased the ratio of Bcl-2/Bax; and activated caspases-3 and-9.Conclusion Sodium valproate inhibited the proliferation of HepG2 cells, triggered mitochondria-dependent HepG2 cell apoptosis and activated JNK.

Patch testing and cross sensitivity study of adverse cutaneous drug reactions due to anticonvulsants: A preliminary report

AIM To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions(ACDR) from common anticonvulsants. METHODS Twenty-four(M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. RESULTS Clinical patterns were exanthematous drug rash with or without systemic involvement(DRESS) in 18(75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis(SJS/TEN) overlap and TEN in 2(8.3%) patients each, SJS and lichenoid drug eruption in 1(4.2%) patient each, respectively. The implicated drugs were phenytoin in 14(58.3%), carbamazepine in 9(37.5%), phenobarbitone in 2(8.3%), and lamotrigine in 1(4.7%) patients,respectively. Twelve(50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6(50%), phenytoin alone in 4(33.3%), phenobarbitone alone in 1(8.3%), and both phenytoin and phenobarbitone in 1(8.33%) patients, respectively. Cross-reactions occurred in 11(92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three(75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. CONCLUSION Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically.