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      Long-Term Valproate Treatment Increases Brain Neuropeptide Y Expression and Decreases Seizure Expression in a Genetic Rat Model of Absence Epilepsy

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          Abstract

          The mechanisms by which valproate, one of the most widely prescribed anti-epileptic drugs, suppresses seizures have not been fully elucidated but may involve up-regulation of neuropeptide Y (NPY). We investigated the effects of valproate treatment in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) on brain NPY mRNA expression and seizure control. GAERS were administered either valproate (42 mg.kg −1 hr −1) or saline continuously for 5 days. Electroencephalograms were recorded for 24 hrs on treatment days 1, 3 and 5 and the percentage of time spent in seizure activity was analysed. NPY mRNA expression was measured in different brain regions using qPCR. Valproate treatment suppressed seizures by 80% in GAERS (p<0.05) and increased NPY mRNA expression in the thalamus (p<0.05) compared to saline treatment. These results demonstrate that long-term valproate treatment results in an upregulation of thalamic expression of NPY implicating this as a potential contributor to the mechanism by which valproate suppresses absence seizures.

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

           K Livak,  T Schmittgen (2001)
          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells.

            Histone deacetylases (HDACs) play important roles in transcriptional regulation and pathogenesis of cancer. Thus, HDAC inhibitors are candidate drugs for differentiation therapy of cancer. Here, we show that the well-tolerated antiepileptic drug valproic acid is a powerful HDAC inhibitor. Valproic acid relieves HDAC-dependent transcriptional repression and causes hyperacetylation of histones in cultured cells and in vivo. Valproic acid inhibits HDAC activity in vitro, most probably by binding to the catalytic center of HDACs. Most importantly, valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients. More over, tumor growth and metastasis formation are significantly reduced in animal experiments. Therefore, valproic acid might serve as an effective drug for cancer therapy.
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              Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.

              Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC(50) for HDAC1 = 0.4 mm). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                9 September 2013
                : 8
                : 9
                Affiliations
                [1 ]Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia
                [2 ]The Department of Medicine, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia
                [3 ]Department of Translational Neurosciences, University of Antwerp, Belgium
                Kaohsiung Chang Gung Memorial Hospital, Taiwan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TJO MJM. Performed the experiments: JE KLP LvR SD. Analyzed the data: JE KLP TJO MJM. Wrote the paper: JE KLP TJO MJM. Reviewed and edited manuscript: JE KLP LvR SD TJO MJM.

                Article
                PONE-D-12-39815
                10.1371/journal.pone.0073505
                3767750
                24039965

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Pages: 6
                Funding
                This work was funded by project grant support from the National Health and Medical Research Council (NHMRC grant #568729) of Australia to MJM and TJO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript” to the Financial Disclosure.
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