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valproic acid attenuates the multiple-organ dysfunction in a rat model of septic shock

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Chinese Medical Journal 2010年第19期123卷 2682-2687页

作者： SHANG You JIANG Yuan-xu Ding Ze-jun Shen Ai-ling XU San-peng YUAN Shi-ying YAO Shang-long Department of Anaesthesiology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China Department of Critical Care Medicine Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China Department of Pathology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430030 China

Background valproic acid （VPA） improves early survival and organ function in a highly lethal poly-trauma and hemorrhagic shock model or other severe insults. We assessed whether VPA could improve organ function in a rat model of septic shock and illustrated the possible mechanisms. Methods Forty Sprague-Dawley rats were randomly assigned to four groups （n=-10）： control group, VPA group, LPS group, and LPS＋VPA group. Lipopolysaccharide （LPS）（10 mg/kg） was injected intravenously to replicate the experimental model of septic shock. Rats were treated with VPA （300 mg/kg, i.v.） or saline. Six hours after LPS injection, blood was sampled for gas analysis, measurement of serum alanine aminotransferase, aspartate aminotransferase, urine nitrogen, creatinine and tumor necrosis factor-alpha. Lung, liver and kidney were collected for histopathological assessment. In addition, myeloperoxidase activity and tumor necrosis factor-α in pulmonary tissue were measured. Acetylation of histone H3 in lung was also evaluated by Western blotting. Results LPS resulted in a significant decrease in PaO2, which was increased by VPA administration followed LPS injection. In addition, LPS also induced an increase in the serum levels of alanine aminotransferase, aspartate aminotransferase, urine nitrogen, creatinine, and tumor necrosis factor-alpha. However, these increases were attenuated in the LPS＋VPA group. The lungs, liver and kidneys from the LPS group were significantly damaged compared with the control group. However, the damage was attenuated in the LPS＋VPA group. Myeloperoxidase activity and tumor necrosis factor-alpha levels in pulmonary tissue increased significantly in the LPS group compared with the control group. These increases were significantly inhibited in the LPS＋VPA group. Acetylation of histone H3 in lung tissue in the LPS group was inhibited compared with the control. However, the level of acetylation of histone H3 in the LPS＋VPA group was markedly elevated in contrast to the LPS group. Conclusions Treatment with VPA c

关键词： valproic acid septic shock inflammation acetylation

valproic acid protects neurons and promotes neuronal regeneration after brachial plexus avulsion

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Neural Regeneration Research 2013年第30期8卷 2838-2848页

作者： Qiang Li Dianxiu Wu Rui Li Xiaojuan Zhu Shusen Cui Department of Hand Surgery China Japan Union Hospital Jilin University Key Laboratory of Molecular Epigenetics of Ministry of Education Institute of Cytology and Genetics Northeast Normal University

valproic acid has been shown to exert neuroprotective effects and promote neurite outgrowth in several peripheral nerve injury models. However, whether valproic acid can exert its beneficial effect on neurons after brachial plexus avulsion injury is currently unknown. In this study, brachial plexus root avulsion models, established in Wistar rats, were administered daily with valproic acid dis-solved in drinking water （300 mg/kg） or normal water. On days 1, 2, 3, 7, 14 and 28 after avulsion injury, tissues of the C 5-T 1 spinal cord segments of the avulsion injured side were harvested to in-vestigate the expression of Bcl-2, c-Jun and growth associated protein 43 by real-time PCR and western blot assay. Results showed that valproic acid significantly increased the expression of Bcl-2 and growth associated protein 43, and reduced the c-Jun expression after brachial plexus avulsion. Our findings indicate that valproic acid can protect neurons in the spinal cord and enhance neuronal regeneration fol owing brachial plexus root avulsion.

关键词： neural regeneration peripheral nerve injury brachial plexus root avulsion spinal cord neurons valproic acid neuroprotection neuronal regeneration Bcl-2 c-Jun GAP-43 grants-supported pa-per neuroregeneration

valproic acid therapy decreases serum 25-hydroxyvitamin D level in female infants and toddlers with epilepsy-a pilot longitudinal study

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The Journal of Biomedical Research 2021年第1期35卷 61-67页

作者： Jinchun Qiu Hongli Guo Ling Li Zeyue Xu Zejun Xu Xia Jing Yahui Hu Xiaoyi Wen Feng Chen Xiaopeng Lu Department of Pharmacy Children's Hospital of Nanjing Medical UniversityNanjingJiangsu 210008China School of Basic Medicine and Clinical Pharmacy China Pharmaceutical UniversityNanjingJiangsu 211198China Department of Neurology Children's Hospital of Nanjing Medical UniversityNanjingJiangsu 210008China.

To evaluate if valproic acid(VPA)therapy is associated with vitamin D deficiency among infants and toddlers with epilepsy,a cross-sectional clinical study was conducted in 25 children with epilepsy taking VPA.Blood levels of calcium,phosphorus,alkaline phosphatase,and 25-hydroxy vitamin D[25(OH)D]and plasma VPA level were measured at 1-to 3-month intervals.At the initial and final measurements,vitamin D deficiency or insufficiency was recognized in 8(32%)and 12(42%),respectively.In girls,a decreasing trend in serum25(OH)D levels(P<0.05)was observed.Polytherapy had a significant negative effect on the longitudinal change of 25(OH)D(P<0.05)in girls.In conclusion,our study indicates that a high proportion of girls after VPA therapy had hypovitaminosis D.

关键词： valproic acid vitamin D hypovitaminosis D epilepsy infants and toddlers

Disruption of Planar Cell Polarity Pathway Attributable to valproic acid-Induced Congenital Heart Disease through Hdac3 Participation in Mice

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Chinese Medical Journal 2018年第17期131卷 2080-2088页

作者： Hong-Yu Ouan Kai-Yu Zhou Tao Wang Yi Zhang Yi-Fei Li Yi-Min Hua Chuan Wang Department of Pediatric Cardiology West China Second University Hospital Sichuan University Chengdu Sichuan 610041 China Cardiac Development and Early Intervention Unit West China Institute of Women and Children's Health West China Second University Hospital Sichuan University Chengdu Sichuan 610041 China Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University) Ministry of Education Chengdu Sichuan 610041 China Key Laboratory of Development and Diseases of Women and Children of Sichuan Province West China Second University Hospital Sichuan University Chengdu Sichuan 610041 China

Background： valproic acid （VPA） exposure during pregnancy has been proven to contribute to congenital heart disease （CHD）. Our previous findings implied that disruption of planar cell polarity （PCP） signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase （HDAC） inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes （Vangl2/Scrib/Rac 1）, subsequently screening out the specific HDACs regulating PCP pathway. Methods： VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day ! 0.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells （undifferentiated rat cardiomyoblasts） were transfected with Hdac1/2/3 specific small interfering RNA （siRNA）. Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Racl mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.Results： VPA could induce CHD （P 〈 0.001） and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression （all P 〈 0.05）. In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression （P 〈 0.01 ）, while knockdown of Hdac 1/2 had no influence （P 〉 0.05）, VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity （P 〈 0.01 ）, while overexpression of Hdac3 could rescue the VPA-induced inhibition （P 〉 0.05）. Conclusion： VPA could inhibit Hdac1/2/3, Vang12/Scrib, or total Hdac activity both in vitro and in

关键词： Congenital Heart Disease Hdacs Planar Cell Polarity valproic acid

Efficacy and mechanisms of Dingxian pill(定痫丸)combined with valproic acid on pentylenetetrazol-induced chronic epilepsy in rats

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Journal of Traditional Chinese Medicine 2023年第2期43卷 286-294页

作者： QU Dongxiao GE Yiqin ZHUO Limin CHEN Liji XUE Yonghua CHENG Jiwei TAO Jie LI Guoyi ZHU Yudan XIAO Qian Department of Neurology and Central Laboratory Putuo HospitalShanghai University of Traditional Chinese MedicineShanghai 200062China Department of Neurosurgery Jiading Branch of Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 201803China Department of Neurology and Central Laboratory Putuo Clinical Medical SchoolAnhui Medical UniversityShanghai 200062China College of Sciences Shanghai UniversityShanghai 200442China

OBJECIVE:To investigate the efficacy and mechanisms of Dingxian pill(定痫丸)combined with valproic acid(VPA)on pentylenetetrazol-induced chronical epilepsy in rats.METHODS:A rat model of epilepsy was established by administering pentylenetetrazol(PTZ)water solution(35 mg/kg).Rats were divided into 4 groups,among which three groups were treated with different drugs once a day for 28 d including Dingxian pill(2.4 g/kg),VPA(0.2 g/kg),or a combination of Dingxian pill(2.4 g/kg)and VPA(0.2 g/kg)respectively,and the control group was given the same volume of saline.Rats in different groups were compared based on animal behavior,electroencephalograms,Morris water maze,immunohistochemistry,transcriptomics and real-time polymerase chain reaction.RSULTS:The combination therapy of Dingxian pill and VPA inhibited PTZ-induced seizure-like behavior and reduced seizure grades more significantly than VPA alone.Compared with the control group,the learning and memory ability of chronic PTZ-induced epileptic rats was improved in all the drug treatment groups,especially in the group that received both Dingxian pill and VPA.Similar to the results of MWM tests,expression of the neuroexcitability marker gene c-Fos was reduced after Dingxian pill and/or VPA treatment,and the effect was most pronounced in the combined treatment group.Transcriptomic analysis revealed that gene expression in the rodent hippocampus,which is involved in epilepsy,was upregulated by combined treatment with Dingxian pill and VPA,compared with VPA treatment alone.CONCLUSION:Our results not only highlight the antiepileptic effects of combined Dingxian pill and VPA treatment,but also shed light on the underlying molecular mechanisms and provide a way to apply Traditional Chinese Medicine in the treatment of epilepsy.

关键词： epilepsy valproic acid learning memory transcriptome Dingxian pill

Scorpion ethanol extract and valproic acid effects on hippocampal glial fibrillary acidic protein expression in a rat model of chronic-kindling epilepsy induced by lithium chloride-pilocarpine

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Neural Regeneration Research 2012年第6期7卷 426-433页

作者： Yi Liang Hongbin Sun Liang Yu Baoming He Yan Xie Department of Neurology Sichuan Academy of Medical Sciences ＆ Sichuan Provincial People＇s Hospital Chengdu 610072 SichuanProvince China

The present study analyzed the effects of ethanol extracts of scorpion on epilepsy prevention and hippocampal expression of glial fibrillary acidic protein in a lithium chloride-pilocarpine epileptic rat model. Results were subsequently compared with valproic acid. Results showed gradually- increased hippocampal glial fibrillary acidic protein expression following model establishment; glial fibrillary acidic protein mRNA expression was significantly increased at 3 days, reached a peak at 7 days, and then gradually decreased thereafter. Ethanol extracts of scorpion doses of 580 and 1 160 mg/kg, as well as 120 mg/kg valproic acid, led to a decreased number of glial fibrillary acidic protein-positive cells and glial fibrillary acidic protein mRNA expression, as well as decreased seizure grades and frequency of spontaneously recurrent seizures. The effects of 1 160 mg/kg ethanol extracts of scorpion were equal to those of 120 mg/kg valproic acid. These results suggested that the anti-epileptic effect of ethanol extracts of scorpion were associated with decreased hippocampal glial fibrillary acidic protein expression in a rat model of lithium chlofide-pilocarpine induced epilepsy.

关键词： Chinese herbs epilepsy glial fibrillary acidic protein lithium chloride-pilocarpine scorpion ethanol extraction valproic acid

Liquid chromatography–tandem mass spectrometry method for simultaneous determination of valproic acid and its ene-metabolites in epilepsy patient plasma

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Journal of Pharmaceutical Analysis 2016年第2期6卷 112-116页

作者： Huan Lu Chong Su Lei Yin Liqiang Gu Jingkai Gu Xiaohui Chen School of Pharmacy Shenyang Pharmaceutical University Research Center for Drug Metabolism College of Life ScienceJilin University Clinical Pharmacology Center Research Institute of Translational Medicine the First Hospital of Jilin University

A simple and high throughput method was developed and validated for simultaneous determination of valproic acid and its two toxicant ene-metabolites, 2-enevalproic acid and 4-enevalproic acid in epilepsy patient plasma using liquid chromatography-tandem mass spectrometry. Probenecid was used as in- ternal standard and solid-phase extraction was selected for sample preparation. A chromatographic separation was performed on an Agilent Poroshell SB-C18 column （50 mm × 4.6 mm i.d., 2.7μm） by an optimized gradient elution at a flow rate of 0.9 mL/min. The total run time was 7 rain. Electrospray ionization was used in negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 143.0→143.0 for valproic acid, m/z 140.9 →140.9 for 2-enevalproic acid and 4-enevalproic acid for their poor fragments, and m/z 283.9→239,9 for probenecid. The results showed good linearity ofvalproic acid, 2-enevalproic acid and 4-enevalproic acid in their respective linear ranges. The correlation coefficients were more than 0.998, The intra- and inter-day precision of the assay was less than 11.0% and the accuracy ranged from 2% to 12%. This analytical method was successfully applied to assay plasma concentrations of valproic acid and its two ene-metabolites in epilepsy patient plasma and used for therapeutic drug monitoring.

关键词： Liquid chromatography-tandem massspectrometry valproic acid 2-enevalproic acid 4-enevalproic acid

Effect of valproic acid on endogenous neural stem cell proliferation in a rat model of spinal cord injury

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Neural Regeneration Research 2009年第7期4卷 513-517页

作者： Guoxin Nan Ming Li Weihong Liao Jiaqiang Qin Yujiang Cao Youqiong Lu Department of Orthopedics Children's Hospital Chongqing Medical University Chongqing 400014 China Research Institute of Surgery Daping Hospital Third Military Medical University of Chinese PLA National Key Laboratory of TraumaBurning and Combined Injury Chongqing 400042 China

BACKGROUND： valproic acid has been reported to decrease apoptosis, promote neuronal differentiation of brain-derived neural stem cells, and inhibit glial differentiation of brain-derived neural stem cells. OBJECTIVE： To investigate the effects of valproic acid on proliferation of endogenous neural stem cells in a rat model of spinal cord injury. DESIGN, TIME AND SETTING： A randomized, controlled, neuropathological study was performed at Key Laboratory of Trauma, Buming, and Combined Injury, Research Institute of Surgery, Daping Hospital, the Third Military Medical University of Chinese PLA between November 2005 and February 2007. MATERIALS： A total of 45 adult, Wistar rats were randomly divided into sham surgery （n = 5）, injury （n = 20）, and valproic acid （n = 20） groups. valproic acid was provided by Sigma, USA. METHODS： Injury was induced to the T10 segment in the injury and valproic acid groups using the metal weight-dropping method. The spinal cord was exposed without contusion in the sham surgery group. Rats in the valproic acid group were intraperitoneally injected with 150 mg/kg valproic acid every 12 hours （twice in total）.MAIN OUTCOME MEASURES： Nestin expression （5 mm from injured center） was detected using immunohistochemistry at 1,3 days, 1, 4, and 8 weeks post-injury. RESULTS： Low expression of nestin was observed in the cytoplasm, but rarely in the white matter of the spinal cord in the sham surgery group. In the injury group, nestin expression was observed in the ependyma and pia mater one day after injury, and expression reached a peak at 1 week （P 〈 0.05）. Expression was primarily observed in the ependymal cells, which expanded towards the white and gray matter of the spinal cord. Nestin expression rapidly decreased by 4 weeks post-injury, and had almost completely disappeared by 8 weeks. At 24 hours after spinal cord injury, there was no significant difference in nestin expression between the valproic acid and injury groups. At 1 week, there was a significant increase in the number of n

关键词： spinal cord injury nestin endogenous neural stem cells valproic acid rats

Simultaneous determination of asenapine and valproic acid in human plasma using LC-MS/MS:Application of the method to support pharmacokinetic study

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Journal of Pharmaceutical Analysis 2013年第6期3卷 394-401页

作者： Ambavaram Vijaya Bhaskar Reddy Nandigam Venugopal Gajulapalle Madhavi Department of Chemistry Sri Venkateswara University

Combination of asenapine with valproic acid received regulatory approval for acute treatment of schizophrenia and maniac episodes of bipolar disorders. A simple LC-MS/MS method was developed and validated for simultaneous quantification of asenapine and valproic acid in human plasma. Internal standards were added to 300 ~L of plasma sample prior to liquid-liquid extraction using methyl tertiary butyl ether （MTBE）. Chromatographic separation was achieved on Phenomenex C18 column （50 mm ~ 4.6 mm, 5 pm） in isocratic mode at 40 ~C. The mobile phase used was 10 mM ammonium formate-acetonitrile （5：95, v/v） at a constant flow rate of 0.8 mL/min monitored on triple quadrupole mass spectrometer, operating in the multiple reaction monitoring （MRM） mode. The injection volume used for LC-MS/MS analysis was 15 taL and the run time was 2.5 min. These low run time and small injection volume suggest the high efficiency of the proposed method. The method was validated over the concentration range of 0.1-10.02ng/mL and 10-20,000ng/mL for asenapine and valproic acid respectively. The method recoveries of asenapine （81.33%）, valproic acid （81.70%）, gliclazide （78.45%） and benzoic acid （79.73） from spiked plasma samples were consistent and reproducible. The application of this method was demonstrated by a pharmacokinetic study in 8 healthy male volunteers with 5 mg asenapine and 250 mg valproic acid administration.

关键词： Asenapine Gliclazide PharmacokineticsBipolar disordersSchizophrenia valproic acid