Generic placeholder image

Current Neuropharmacology


ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Review Article

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

Author(s): Fan-Cheng Kong, Chun-Lai Ma* and Ming-Kang Zhong

Volume 18 , Issue 2 , 2020

Page: [153 - 166] Pages: 14

DOI: 10.2174/1570159X17666191010094849

Price: $65


An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.

Keywords: Antiepileptic drug, DNA methylation, histone modification, untranslated RNA, molecular mechanism, application.

Graphical Abstract
Rogawski, M.A.; Löscher, W. The neurobiology of antiepileptic drugs. Nat. Rev. Neurosci., 2004, 5(7), 553-564.
[] [PMID: 15208697]
Bird, A. Perceptions of epigenetics. Nature, 2007, 447(7143), 396-398.
[] [PMID: 17522671]
Esteller, M. Epigenetics in cancer. N. Engl. J. Med., 2008, 358(11), 1148-1159.
[] [PMID: 18337604]
Weichert, W.; Röske, A.; Gekeler, V.; Beckers, T.; Ebert, M.P.; Pross, M.; Dietel, M.; Denkert, C.; Röcken, C. Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis. Lancet Oncol., 2008, 9(2), 139-148.
[] [PMID: 18207460]
Rong, H.; Liu, T.B.; Yang, K.J.; Yang, H.C.; Wu, D.H.; Liao, C.P.; Hong, F.; Yang, H.Z.; Wan, F.; Ye, X.Y.; Xu, D.; Zhang, X.; Chao, C.A.; Shen, Q.J. MicroRNA-134 plasma levels before and after treatment for bipolar mania. J. Psychiatr. Res., 2011, 45(1), 92-95.
[] [PMID: 20546789]
Suraweera, A.; O’Byrne, K.J.; Richard, D.J. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Front. Oncol., 2018, 8, 92.
[] [PMID: 29651407]
Chou, T.C.; Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul., 1984, 22, 27-55.
[] [PMID: 6382953]
Masterpasqua, F. Psychology and Epigenetics. Rev. Gen. Psychol., 2009, 13(3), 194-201.
Pitkänen, A.; Löscher, W.; Vezzani, A.; Becker, A.J.; Simonato, M.; Lukasiuk, K.; Gröhn, O.; Bankstahl, J.P.; Friedman, A.; Aronica, E.; Gorter, J.A.; Ravizza, T.; Sisodiya, S.M.; Kokaia, M.; Beck, H. Advances in the development of biomarkers for epilepsy. Lancet Neurol., 2016, 15(8), 843-856.
[] [PMID: 27302363]
Issa, J-P.J.; Kantarjian, H.M.; Targeting, D.N.A. Targeting DNA methylation. Clin. Cancer Res., 2009, 15(12), 3938-3946.
[] [PMID: 19509174]
Xu, W.S.; Parmigiani, R.B.; Marks, P.A. Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene, 2007, 26(37), 5541-5552.
[] [PMID: 17694093]
Eyal, S.; Yagen, B.; Sobol, E.; Altschuler, Y.; Shmuel, M.; Bialer, M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia, 2004, 45(7), 737-744.
[] [PMID: 15230695]
Szyf, M.; Epigenetics, D.N.A. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu. Rev. Pharmacol. Toxicol., 2009, 49(1), 243-263.
[] [PMID: 18851683]
Kacevska, M.; Ivanov, M.; Ingelman‐Sundberg, M. J. C. P. Therapeutics, Perspectives on epigenetics and its relevance to adverse drug reactions 2011, 89(6), 902-907.
Watson, R.E.; Goodman, J.I. Epigenetics and DNA methylation come of age in toxicology. Toxicol. Sci., 2002, 67(1), 11-16.
[] [PMID: 11961211]
Jones, P.A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet., 2012, 13(7), 484-492.
[] [PMID: 22641018]
Bestor, T.H. The DNA methyl transferases of mammals. Hum. Mol. Genet., 2000, 9(16), 2395-2402.
[] [PMID: 11005794]
Goldberg, A.D.; Allis, C.D.; Bernstein, E. Epigenetics: a landscape takes shape. Cell, 2007, 128(4), 635-638.
[] [PMID: 17320500]
Vidaki, A.; Daniel, B.; Court, D.S. Forensic DNA methylation profiling--potential opportunities and challenges. Forensic Sci. Int. Genet., 2013, 7(5), 499-507.
[] [PMID: 23948320]
Mahna, D.; Puri, S.; Sharma, S. DNA methylation signatures: Biomarkers of drug and alcohol abuse. Mutat. Res., 2018, 777, 19-28.
[] [PMID: 30115428]
Dong, E.; Chen, Y.; Gavin, D.P.; Grayson, D.R.; Guidotti, A. Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. Epigenetics, 2010, 5(8), 730-735.
[] [PMID: 20716949]
Dezsi, G.; Ozturk, E.; Stanic, D.; Powell, K.L.; Blumenfeld, H.; O’Brien, T.J.; Jones, N.C. Ethosuximide reduces epileptogenesis and behavioral comorbidity in the GAERS model of genetic generalized epilepsy. Epilepsia, 2013, 54(4), 635-643.
[] [PMID: 23464801]
Perng, W.; Villamor, E.; Shroff, M.R.; Nettleton, J.A.; Pilsner, J.R.; Liu, Y.; Diez-Roux, A.V. Dietary intake, plasma homocysteine, and repetitive element DNA methylation in the multi-ethnic study of atherosclerosis (MESA). Nutr. Metab. Cardiovasc. Dis., 2014, 24(6), 614-622.
[] [PMID: 24477006]
Ni, G.; Qin, J.; Li, H.; Chen, Z.; Zhou, Y.; Fang, Z.; Chen, Y.; Zhou, J.; Huang, M.; Zhou, L. Effects of antiepileptic drug monotherapy on one-carbon metabolism and DNA methylation in patients with epilepsy. PLoS One, 2015, 10(4)e0125656
[] [PMID: 25915064]
Ni, G.; Qin, J.; Chen, Z.; Li, H.; Zhou, J.; Huang, M.; Zhou, L. Associations between genetic variation in one-carbon metabolism and leukocyte DNA methylation in valproate-treated patients with epilepsy. Clin. Nutrition, (Edinburgh, Scotland), 2018, 37(1), 308-312.
Miousse, I.R.; Murphy, L.A.; Lin, H.; Schisler, M.R.; Sun, J.; Chalbot, M.G.; Sura, R.; Johnson, K.; LeBaron, M.J.; Kavouras, I.G.; Schnackenberg, L.K.; Beger, R.D.; Rasoulpour, R.J.; Koturbash, I. Dose-response analysis of epigenetic, metabolic, and apical endpoints after short-term exposure to experimental hepatotoxicants. Food Chem. Toxicol., 2017, 109(Pt 1), 690-702.
Bogdanović, O.; Veenstra, G.J.C. DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma, 2009, 118(5), 549-565.
[] [PMID: 19506892]
Pucci, M.; Rapino, C.; Di Francesco, A.; Dainese, E.; D’Addario, C.; Maccarrone, M. Epigenetic control of skin differentiation genes by phytocannabinoids. Br. J. Pharmacol., 2013, 170(3), 581-591.
[] [PMID: 23869687]
Fan, J.; Krautkramer, K.A.; Feldman, J.L.; Denu, J.M. Metabolic regulation of histone post-translational modifications. ACS Chem. Biol., 2015, 10(1), 95-108.
[] [PMID: 25562692]
Seto, E.; Yoshida, M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol., 2014, 6(4) a018713
[] [PMID: 24691964]
Göttlicher, M.; Minucci, S.; Zhu, P.; Krämer, O.H.; Schimpf, A.; Giavara, S.; Sleeman, J.P.; Lo Coco, F.; Nervi, C.; Pelicci, P.G.; Heinzel, T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J., 2001, 20(24), 6969-6978.
[] [PMID: 11742974]
Beutler, A.S.; Li, S.; Nicol, R.; Walsh, M.J. Carbamazepine is an inhibitor of histone deacetylases. Life Sci., 2005, 76(26), 3107-3115.
[] [PMID: 15850602]
Bang, S.R.; Ambavade, S.D.; Jagdale, P.G.; Adkar, P.P.; Waghmare, A.B.; Ambavade, P.D. Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer’s disease. Pharmacol. Biochem. Behav., 2015, 134, 65-69.
[] [PMID: 25931268]
Eyal, S.; Yagen, B.; Sobol, E.; Altschuler, Y.; Shmuel, M.; Bialer, M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia, 2004, 45(7), 737-744.
[] [PMID: 15230695]
Matsui, M.; Corey, D.R. Non-coding RNAs as drug targets. Nat. Rev. Drug Discov., 2017, 16(3), 167-179.
[] [PMID: 27444227]
van Vliet, E.A.; Puhakka, N.; Mills, J.D.; Srivastava, P.K.; Johnson, M.R.; Roncon, P.; Das Gupta, S.; Karttunen, J.; Simonato, M.; Lukasiuk, K.; Gorter, J.A.; Aronica, E.; Pitkänen, A. Standardization procedure for plasma biomarker analysis in rat models of epileptogenesis: Focus on circulating microRNAs. Epilepsia, 2017, 58(12), 2013-2024.
[] [PMID: 28960286]
Pereira, D.M.; Rodrigues, P.M.; Borralho, P.M.; Rodrigues, C.M.P. Delivering the promise of miRNA cancer therapeutics. Drug Discov. Today, 2013, 18(5-6), 282-289.
[] [PMID: 23064097]
Lu, M.; Zhang, Q.; Deng, M.; Miao, J.; Guo, Y.; Gao, W.; Cui, Q. An analysis of human microRNA and disease associations. PLoS One, 2008, 3(10)e3420
[] [PMID: 18923704]
Oikawa, H.; Goh, W.W.; Lim, V.K.; Wong, L.; Sng, J.C. Valproic acid mediates miR-124 to down-regulate a novel protein target, GNAI1. Neurochem. Int., 2015, 91, 62-71.
[] [PMID: 26519098]
Lin, T.; Ren, Q.; Zuo, W.; Jia, R.; Xie, L.; Lin, R.; Zhao, H.; Chen, J.; Lei, Y.; Wang, P.; Dong, H.; Huang, L.; Cai, J.; Peng, Y.; Yu, Z.; Tan, J.; Wang, S. Valproic acid exhibits anti-tumor activity selectively against EGFR/ErbB2/ErbB3-coexpressing pancreatic cancer via induction of ErbB family members-targeting microRNAs. J. Exp. Clin. Cancer Res., 2019, 38(1), 150.
[] [PMID: 30961642]
Hara, Y.; Ago, Y.; Takano, E.; Hasebe, S.; Nakazawa, T.; Hashimoto, H.; Matsuda, T.; Takuma, K. Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain. Mol. Autism, 2017, 8, 33.
[] [PMID: 28670439]
Pouche, L.; Vitobello, A.; Romer, M.; Glogovac, M.; MacLeod, A.K.; Ellinger-Ziegelbauer, H.; Westphal, M.; Dubost, V.; Stiehl, D.P.; Dumotier, B.; Fekete, A.; Moulin, P.; Zell, A.; Schwarz, M.; Moreno, R.; Huang, J.T.J.; Elcombe, C.R.; Henderson, C.J.; Roland Wolf, C.; Moggs, J.G.; Terranova, R. Xenobiotic CAR Activators induce Dlk1-Dio3 locus noncoding RNA expression in mouse liver. Toxicol. Sci., 2017, 158(2), 367-378.
Monroy-Arreola, A.; Durán-Figueroa, N.V.; Méndez-Flores, S.; Domínguez-Cherit, J.; Watkinson, J.; Badillo-Corona, J.A.; Whitaker, P.; Naisbitt, D.J.; Castrejón-Flores, J.L. Up-Regulation of T-cell activation microRNAs in drug-specific CD4+ T-cells from Hypersensitive patients. Chem. Res. Toxicol., 2018, 31(6), 454-461.
[] [PMID: 29644860]
Iori, V.; Iyer, A.M.; Ravizza, T.; Beltrame, L.; Paracchini, L.; Marchini, S.; Cerovic, M.; Hill, C.; Ferrari, M.; Zucchetti, M.; Molteni, M.; Rossetti, C.; Brambilla, R.; Steve, W.H.; D’Incalci, M.; Aronica, E.; Vezzani, A. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol. Dis., 2017, 99, 12-23.
[] [PMID: 27939857]
Xu, M.; Li, D.; Yang, C.; Ji, J.S. MicroRNA-34a Inhibition of the TLR signaling pathway Via CXCL10 suppresses breast cancer Cell invasion and migration. Cell. Physiol. Biochem., 2018, 46(3), 1286-1304.
Cheng, C.J.; Saltzman, W.M.; Slack, F.J. Canonical and non-canonical barriers facing antimiR cancer therapeutics. Curr. Med. Chem., 2013, 20(29), 3582-3593.
[] [PMID: 23745563]
Ngugi, A.K.; Bottomley, C.; Kleinschmidt, I.; Sander, J.W.; Newton, C.R. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia, 2010, 51(5), 883-890.
[] [PMID: 20067507]
Kwan, P.; Brodie, M.J. Early identification of refractory epilepsy. N. Engl. J. Med., 2000, 342(5), 314-319.
[] [PMID: 10660394]
Pitkänen, A.; Löscher, W.; Vezzani, A.; Becker, A.J.; Simonato, M.; Lukasiuk, K.; Gröhn, O.; Bankstahl, J.P.; Friedman, A.; Aronica, E.; Gorter, J.A.; Ravizza, T.; Sisodiya, S.M.; Kokaia, M.; Beck, H. Advances in the development of biomarkers for epilepsy. Lancet Neurol., 2016, 15(8), 843-856.
[] [PMID: 27302363]
Grimminger, T.; Pernhorst, K.; Surges, R.; Niehusmann, P.; Priebe, L.; von Lehe, M.; Hoffmann, P.; Cichon, S.; Schoch, S.; Becker, A.J. Levetiracetam resistance: Synaptic signatures & corresponding promoter SNPs in epileptic hippocampi. Neurobiol. Dis., 2013, 60, 115-125.
[] [PMID: 24018139]
You, D.; Wen, X.; Gorczyca, L.; Morris, A.; Richardson, J.R.; Aleksunes, L.M. Increased MDR1 transporter expression in human brain endothelial cells through enhanced histone acetylation and activation of aryl hydrocarbon receptor signaling. Mol. Neurobiol., 2019, 56(10), 6986-7002.
[] [PMID: 30963442]
Tan, N.N.; Tang, H.L.; Lin, G.W.; Chen, Y.H.; Lu, P.; Li, H.J.; Gao, M.M.; Zhao, Q.H.; Yi, Y.H.; Liao, W.P.; Long, Y.S. Epigenetic downregulation of Scn3a expression by valproate: A possible role in its anticonvulsant activity. Mol. Neurobiol., 2017, 54(4), 2831-2842.
[] [PMID: 27013471]
Ma, Y. The Challenge of microRNA as a biomarker of epilepsy. Curr. Neuropharmacol., 2018, 16(1), 37-42.
[PMID: 28676013]
Bialer, M.; Johannessen, S.I.; Koepp, M.J.; Levy, R.H.; Perucca, E.; Tomson, T.; White, H.S. Progress report on new antiepileptic drugs: A summary of the fourteenth eilat conference on new antiepileptic drugs and devices (EILAT XIV). I. Drugs in preclinical and early clinical development. Epilepsia, 2018, 59(10), 1811-1841.
[] [PMID: 30368792]
Bolden, J.E.; Peart, M.J.; Johnstone, R.W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov., 2006, 5(9), 769-784.
[] [PMID: 16955068]
Sun, L.; He, Q.; Tsai, C.; Lei, J.; Chen, J.; Vienna, M.L.; Coy, D.H. HDAC inhibitors suppressed small cell lung cancer cell growth and enhanced the suppressive effects of receptor-targeting cytotoxins via upregulating somatostatin receptor II. Am. J. Transl. Res., 2018, 10(2), 545-553.
[PMID: 29511449]
Eckert, M.; Klumpp, L.; Huber, S.M. Cellular effects of the antiepileptic drug valproic acid in glioblastoma. Cell. Physiol. Biochem., 2017, 44(4), 1591-1605.
Aztopal, N.; Erkisa, M.; Erturk, E.; Ulukaya, E.; Tokullugil, A.H.; Ari, F. Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells. Chem. Biol. Interact., 2018, 280, 51-58.
[] [PMID: 29225137]
La Noce, M.; Paino, F.; Mele, L.; Papaccio, G.; Regad, T.; Lombardi, A.; Papaccio, F.; Desiderio, V.; Tirino, V. HDAC2 depletion promotes osteosarcoma’s stemness both in vitro and in vivo: a study on a putative new target for CSCs directed therapy. J. Exp. Clin. Cancer Res., 2018, 37(1), 296.
[] [PMID: 30509303]
Terranova-Barberio, M.; Pecori, B.; Roca, M.S.; Imbimbo, S.; Bruzzese, F.; Leone, A.; Muto, P.; Delrio, P.; Avallone, A.; Budillon, A.; Di Gennaro, E. Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53. J. Exp. Clin. Cancer Res., 2017, 36(1), 177.
[] [PMID: 29212503]
Halaburková, A.; Jendželovský, R.; Kovaľ, J.; Herceg, Z.; Fedoročko, P.; Ghantous, A. Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A. Clin. Epigenetics, 2017, 9, 62.
[] [PMID: 28603560]
Cha, H.Y.; Lee, B.S.; Chang, J.W.; Park, J.K.; Han, J.H.; Kim, Y.S.; Shin, Y.S.; Byeon, H.K.; Kim, C.H. Downregulation of Nrf2 by the combination of TRAIL and Valproic acid induces apoptotic cell death of TRAIL-resistant papillary thyroid cancer cells via suppression of Bcl-xL. Cancer Lett., 2016, 372(1), 65-74.
[] [PMID: 26721202]
Makarević, J.; Rutz, J.; Juengel, E.; Maxeiner, S.; Tsaur, I.; Chun, F.K.; Bereiter-Hahn, J.; Blaheta, R.A. Influence of the HDAC Inhibitor valproic Acid on the growth and proliferation of temsirolimus-resistant prostate cancer cells In Vitro. Cancers (Basel), 2019, 11(4)E566
[] [PMID: 31010254]
Sajadpoor, Z.; Amini-Farsani, Z.; Teimori, H.; Shamsara, M.; Sangtarash, M.H.; Ghasemi-Dehkordi, P.; Yadollahi, F. Valproic acid promotes apoptosis and cisplatin sensitivity through downregulation of H19 noncoding RNA in ovarian A2780 cells. Appl. Biochem. Biotechnol., 2018, 185(4), 1132-1144.
[] [PMID: 29468525]
Zhuo, W.; Zhang, L.; Zhu, Y.; Xie, Q.; Zhu, B.; Chen, Z. Valproic acid, an inhibitor of class I histone deacetylases, reverses acquired Erlotinib-resistance of lung adenocarcinoma cells: A connectivity Mapping analysis and an experimental study. Am. J. Cancer Res., 2015, 5(7), 2202-2211.
[PMID: 26328250]
Matsuda, Y.; Wakai, T.; Kubota, M.; Osawa, M.; Hirose, Y.; Sakata, J.; Kobayashi, T.; Fujimaki, S.; Takamura, M.; Yamagiwa, S.; Aoyagi, Y. Valproic acid overcomes transforming growth factor-β-mediated sorafenib resistance in hepatocellular carcinoma. Int. J. Clin. Exp. Pathol., 2014, 7(4), 1299-1313.
[PMID: 24817927]
Wang, Y.; Kuramitsu, Y.; Kitagawa, T.; Tokuda, K.; Baron, B.; Akada, J.; Nakamura, K. The histone deacetylase inhibitor Valproic acid sensitizes gemcitabine-Induced Cytotoxicity in Gemcitabine-resistant pancreatic cancer cells possibly through inhibition of the DNA repair protein gamma-H2AX. Target. Oncol., 2015, 10(4), 575-581.
[] [PMID: 25940934]
Blaheta, R.A.; Michaelis, M.; Natsheh, I.; Hasenberg, C.; Weich, E.; Relja, B.; Jonas, D.; Doerr, H.W.; Cinatl, J. Jr Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium. Br. J. Cancer, 2007, 96(11), 1699-1706.
[] [PMID: 17505515]
Kim, Y.H.; Kim, T.; Joo, J.D.; Han, J.H.; Kim, Y.J.; Kim, I.A.; Yun, C.H.; Kim, C.Y. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer, 2015, 121(17), 2926-2932.
[] [PMID: 25975354]
Scicchitano, B.M.; Sorrentino, S.; Proietti, G.; Lama, G.; Dobrowolny, G.; Catizone, A.; Binda, E.; Larocca, L.M.; Sica, G. Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis. Cancer Cell Int., 2018, 18(1), 136.
[] [PMID: 30214378]
Rizzo, A.; Donzelli, S.; Girgenti, V.; Sacconi, A.; Vasco, C.; Salmaggi, A.; Blandino, G.; Maschio, M.; Ciusani, E. In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells. Journal of experimental & clinical cancer research. CR (East Lansing Mich.), 2017, 36(1), 76.
Bellissimo, T.; Ganci, F.; Gallo, E.; Sacconi, A.; Tito, C.; De Angelis, L.; Pulito, C.; Masciarelli, S.; Diso, D.; Anile, M.; Petrozza, V.; Giangaspero, F.; Pescarmona, E.; Facciolo, F.; Venuta, F.; Marino, M.; Blandino, G.; Fazi, F. Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation. Mol. Cancer, 2017, 16(1), 88.
[] [PMID: 28486946]
Mula, M.; Monaco, F. J. E. D. Antiepileptic drugs and psychopathology of epilepsy: an update. 2009, 11(1), 1-9.
Boyadjieva, N.; Varadinova, M. Epigenetics of psychoactive drugs. J. Pharm. Pharmacol., 2012, 64(10), 1349-1358.
[] [PMID: 22943166]
Severinsen, J.E.; Bjarkam, C.R.; Kiaer-Larsen, S.; Olsen, I.M.; Nielsen, M.M.; Blechingberg, J.; Nielsen, A.L.; Holm, I.E.; Foldager, L.; Young, B.D.; Muir, W.J.; Blackwood, D.H.; Corydon, T.J.; Mors, O.; Børglum, A.D. Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder. Mol. Psychiatry, 2006, 11(12), 1126-1138.
[] [PMID: 16924267]
Dyrvig, M.; Qvist, P.; Lichota, J.; Larsen, K.; Nyegaard, M.; Børglum, A.D.; Christensen, J.H. DNA Methylation Analysis of BRD1 Promoter Regions and the Schizophrenia rs138880 Risk Allele. PLoS One, 2017, 12(1) e0170121
[] [PMID: 28095495]
Zong, L.; Zhou, L.; Hou, Y.; Zhang, L.; Jiang, W.; Zhang, W.; Wang, L.; Luo, X.; Wang, S.; Deng, C.; Peng, Z.; Li, S.; Hu, J.; Zhao, H.; Zhao, C. Genetic and epigenetic regulation on the transcription of GABRB2: Genotype-dependent hydroxymethylation and methylation alterations in schizophrenia. J. Psychiatr. Res., 2017, 88, 9-17.
[] [PMID: 28063323]
Stark, T.; Ruda-Kucerova, J.; Iannotti, F.A.; D’Addario, C.; Di Marco, R.; Pekarik, V.; Drazanova, E.; Piscitelli, F.; Bari, M.; Babinska, Z.; Giurdanella, G.; Di Bartolomeo, M.; Salomone, S.; Sulcova, A.; Maccarrone, M.; Wotjak, C.T.; Starcuk, Z., Jr; Drago, F.; Mechoulam, R.; Di Marzo, V.; Micale, V. Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia. Neuropharmacology, 2019, 146, 212-221.
[] [PMID: 30496751]
Ookubo, M.; Kanai, H.; Aoki, H.; Yamada, N. Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes. J. Psychiatr. Res., 2013, 47(9), 1204-1214.
[] [PMID: 23777937]
Bahna, S.G.; Niles, L.P. Epigenetic induction of melatonin MT1 receptors by valproate: Neurotherapeutic implications. Eur. Neuropsychopharmacol., 2017, 27(8), 828-832.
Houtepen, L.C.; van Bergen, A.H.; Vinkers, C.H.; Boks, M.P. DNA methylation signatures of mood stabilizers and antipsychotics in bipolar disorder. Epigenomics, 2016, 8(2), 197-208.
[] [PMID: 26792232]
Nikolian, V.C.; Dennahy, I.S.; Weykamp, M.; Williams, A.M.; Bhatti, U.F.; Eidy, H.; Ghandour, M.; Chtraklin, K.; Li, Y.; Alam, H.B. Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock. J. Trauma Acute Care Surg., 2018, 86(2), 232-239.
[PMID: 30399139]
Leng, Y.; Wang, J.; Wang, Z.; Liao, H.M.; Wei, M.; Leeds, P.; Chuang, D.M. Valproic acid and other HDAC Inhibitors upregulate FGF21 gene expression and promote process elongation in glia by inhibiting HDAC2 and 3. Int. J. Neuropsychopharmacol., 2016, 19(8), 13.
[] [PMID: 27207921]
da Silva, V.K.; de Freitas, B.S.; Dornelles, V.C.; Kist, L.W.; Bogo, M.R.; Silva, M.C.; Streck, E.L.; Hallak, J.E.; Zuardi, A.W.; Crippa, J.A.S.; Schröder, N. Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol. Brain Res. Bull., 2018, 139, 1-8.
[] [PMID: 29374603]
Green, A.L.; Zhan, L.; Eid, A.; Zarbl, H.; Guo, G.L.; Richardson, J.R. Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1. Neuropharmacology, 2017, 125, 189-196.
[] [PMID: 28743636]
Armon, C.; Shin, C.; Miller, P.; Carwile, S.; Brown, E.; Edinger, J.D.; Paul, R.G. Reversible parkinsonism and cognitive impairment with chronic valproate use. Neurology, 1996, 47(3), 626-635.
[] [PMID: 8797455]
Kee, H.J.; Kook, H. Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy. J. Biomed. Biotechnol., 2011.2011928326
[] [PMID: 21151616]
McKinsey, T.A. Therapeutic potential for HDAC inhibitors in the heart. Annu. Rev. Pharmacol. Toxicol., 2012, 52, 303-319.
[] [PMID: 21942627]
Azghandi, S.; Prell, C.; van der Laan, S.W.; Schneider, M.; Malik, R.; Berer, K.; Gerdes, N.; Pasterkamp, G.; Weber, C.; Haffner, C.; Dichgans, M. Deficiency of the stroke relevant HDAC9 gene attenuates atherosclerosis in accord with allele-specific effects at 7p21.1. Stroke, 2015, 46(1), 197-202.
[] [PMID: 25388417]
Brookes, R.L.; Crichton, S.; Wolfe, C.D.A.; Yi, Q.; Li, L.; Hankey, G.J.; Rothwell, P.M.; Markus, H.S. Sodium valproate, a histone deacetylasei, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke, 2018, 49(1), 54-61.
[] [PMID: 29247141]
Choi, J.; Park, S.; Kwon, T. K.; Sohn, S. I.; Park, K. M.; Kim, J. I. Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis Intl. J. Obesity (2005), 2017, 41(11), 1702-1709.
Scholz, B.; Schulte, J.S.; Hamer, S.; Himmler, K.; Pluteanu, F.; Seidl, M.D.; Stein, J.; Wardelmann, E.; Hammer, E.; Völker, U.; Müller, F.U. HDAC (Histone deacetylase) inhibitor valproic acid attenuates atrial remodeling and delays the onset of atrial fibrillation in mice. Circ Arrhythm Electrophysiol, 2019, 12(3) e007071
[] [PMID: 30879335]
Cho, H.M.; Seok, Y.M.; Lee, H.A.; Song, M.; Kim, I. Repression of transcriptional activity of forkhead Box O1 by histone deacetylase inhibitors ameliorates hyperglycemia in Type 2 diabetic rats. Int. J. Mol. Sci., 2018, 19(11) E3539
[] [PMID: 30424007]
Nguyễn-Thanh, T.; Kim, D.; Lee, S.; Kim, W.; Park, S.K.; Kang, K.P. Inhibition of histone deacetylase 1 ameliorates renal tubulointerstitial fibrosis via modulation of inflammation and extracellular matrix gene transcription in mice. Int. J. Mol. Med., 2018, 41(1), 95-106.
[PMID: 29115561]
Hemberger, M.; Dean, W.; Reik, W. Epigenetic dynamics of stem cells and cell lineage commitment: digging Waddington’s canal. Nat. Rev. Mol. Cell Biol., 2009, 10(8), 526-537.
[] [PMID: 19603040]
Hsieh, J.; Nakashima, K.; Kuwabara, T.; Mejia, E.; Gage, F.H. Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc. Natl. Acad. Sci. USA, 2004, 101(47), 16659-16664.
[] [PMID: 15537713]
Zhang, X.; He, X.; Li, Q.; Kong, X.; Ou, Z.; Zhang, L.; Gong, Z.; Long, D.; Li, J.; Zhang, M.; Ji, W.; Zhang, W.; Xu, L.; Xuan, A. PI3K/AKT/mTOR Signaling mediates valproic Acid-Induced neuronal differentiation of neural stem cells through epigenetic modifications. Stem Cell Reports, 2017, 8(5), 1256-1269.
[] [PMID: 28494938]
Vukićević, V.; Qin, N.; Balyura, M.; Eisenhofer, G.; Wong, M.L.; Licinio, J.; Bornstein, S.R.; Ehrhart-Bornstein, M. Valproic acid enhances neuronal differentiation of sympathoadrenal progenitor cells. Mol. Psychiatry, 2015, 20(8), 941-950.
[] [PMID: 25707399]
Zhang, C.; Zhang, E.; Yang, L.; Tu, W.; Lin, J.; Yuan, C.; Bunpetch, V.; Chen, X.; Ouyang, H. Histone deacetylase inhibitor treated cell sheet from mouse tendon stem/progenitor cells promotes tendon repair. Biomaterials, 2018, 172, 66-82.
[] [PMID: 29723756]
Jamal, I.; Kumar, V.; Vatsa, N.; Shekhar, S.; Singh, B.K.; Sharma, A.; Jana, N.R. Rescue of altered HDAC activity recovers behavioural abnormalities in a mouse model of Angelman syndrome. Neurobiol. Dis., 2017, 105, 99-108.
[] [PMID: 28576709]
Chen, S.; Ye, J.; Chen, X.; Shi, J.; Wu, W.; Lin, W.; Lin, W.; Li, Y.; Fu, H.; Li, S. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J. Neuroinflammation, 2018, 15(1), 150.
[] [PMID: 29776446]
Raut, A.; Khanna, A. Enhanced expression of hepatocyte-specific microRNAs in valproic acid mediated hepatic trans-differentiation of human umbilical cord derived mesenchymal stem cells. Exp. Cell Res., 2016, 343(2), 237-247.
[] [PMID: 27001466]
Ideta-Otsuka, M.; Igarashi, K.; Narita, M.; Hirabayashi, Y. Epigenetic toxicity of environmental chemicals upon exposure during development - Bisphenol A and valproic acid may have epigenetic effects. Food Chem. Toxicol., 2017, 109(Pt 1), 812-816.
Marczylo, E.L.; Jacobs, M.N.; Gant, T.W. Environmentally induced epigenetic toxicity: potential public health concerns. Crit. Rev. Toxicol., 2016, 46(8), 676-700.
[] [PMID: 27278298]
Herceg, Z.; Lambert, M-P.; van Veldhoven, K.; Demetriou, C.; Vineis, P.; Smith, M.T.; Straif, K.; Wild, C.P. Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. Carcinogenesis, 2013, 34(9), 1955-1967.
[] [PMID: 23749751]
Some thyrotropic agents. IARC Monogr. Eval. Carcinog. Risks Hum., 2001, 79, i-iv, 1-725.
[PMID: 11766267]
Holsapple, M.P.; Pitot, H.C.; Cohen, S.M.; Boobis, A.R.; Klaunig, J.E.; Pastoor, T.; Dellarco, V.L.; Dragan, Y.P. Mode of action in relevance of rodent liver tumors to human cancer risk. Toxicol. Sci., 2006, 89(1), 51-56.
[] [PMID: 16221960]
Tomson, T.; Battino, D. Teratogenic effects of antiepileptic drugs. Lancet Neurol., 2012, 11(9), 803-813.
[] [PMID: 22805351]
Dansky, L.; Rosenblatt, D.; Andermann, E.J.N. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology, 1992, 42(4)(Suppl. 5), 32-42.
Al-Ansari, A.; Robertson, N.P. Anti-epileptics and pregnancy: an update. J. Neurol., 2018, 265(11), 2749-2751.
[] [PMID: 30238267]
Martínez-Frías, M.L. Can our understanding of epigenetics assist with primary prevention of congenital defects? J. Med. Genet., 2010, 47(2), 73-80.
[] [PMID: 19755430]
Tung, E.W.; Winn, L.M. Epigenetic modifications in valproic acid-induced teratogenesis. Toxicol. Appl. Pharmacol., 2010, 248(3), 201-209.
[] [PMID: 20705080]
Nicolini, C.; Fahnestock, M. The valproic acid-induced rodent model of autism. Exper. Neurol., 2018, 229(Pt A), 217-227.
Hirsch, M.M.; Deckmann, I.; Fontes-Dutra, M.; Bauer-Negrini, G.; Della-Flora Nunes, G.; Nunes, W.; Rabelo, B.; Riesgo, R.; Margis, R.; Bambini-Junior, V.; Gottfried, C. Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA. Food Chemical. Toxicol., 2018, 115, 336-343.
Yadav, S.; Tiwari, V.; Singh, M.; Yadav, R.K.; Roy, S.; Devi, U.; Gautam, S.; Rawat, J.K.; Ansari, M.N.; Saeedan, A.S.; Prakash, A.; Saraf, S.A.; Kaithwas, G. Comparative efficacy of alpha-linolenic acid and gamma-linolenic acid to attenuate valproic acid-induced autism-like features. J. Physiol. Biochem., 2017, 73(2), 187-198.
[] [PMID: 27878518]
Yu, W.H.; Ho, Y.L.; Huang, P.T.; Chu, S.L.; Tsai, H.J.; Liou, H.H. The phosphorylation state of GSK3β serine 9 correlated to the Development of valproic acid-associated fetal cardiac teratogenicity, fetal VPA syndrome, rescued by folic acid administration. Cardiovasc. Toxicol., 2016, 16(1), 34-45.
[] [PMID: 25724324]
van Breda, S.G.J.; Claessen, S.M.H.; van Herwijnen, M.; Theunissen, D.H.J.; Jennen, D.G.J.; de Kok, T.M.C.M.; Kleinjans, J.C.S. Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology, 2018, 393, 160-170.
[] [PMID: 29154799]
Palsamy, P.; Bidasee, K.R.; Shinohara, T. Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells. Exp. Eye Res., 2014, 121, 26-34.
[] [PMID: 24525405]
Eisses, J.F.; Criscimanna, A.; Dionise, Z.R.; Orabi, A.I.; Javed, T.A.; Sarwar, S.; Jin, S.; Zhou, L.; Singh, S.; Poddar, M.; Davis, A.W.; Tosun, A.B.; Ozolek, J.A.; Lowe, M.E.; Monga, S.P.; Rohde, G.K.; Esni, F.; Husain, S.Z. Valproic acid Limits pancreatic recovery after pancreatitis by inhibiting histone deacetylases and preventing acinar redifferentiation Programs. Am. J. Pathol., 2015, 185(12), 3304-3315.
[] [PMID: 26476347]
Sakakibara, Y.; Katoh, M.; Kondo, Y.; Nadai, M. Effects of phenobarbital on expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in rat brain. Drug Metab. Dispos., 2016, 44(3), 370-377.
[] [PMID: 26684499]
Ma, T.; Huang, C.; Xu, Q.; Yang, Y.; Liu, Y.; Meng, X.; Li, J.; Ye, M.; Liang, H. Suppression of BMP-7 by histone deacetylase 2 promoted apoptosis of renal tubular epithelial cells in acute kidney injury. Cell Death Dis., 2017, 8(10) e3139
[] [PMID: 29072686]
Anderson, S.J.; Feye, K.M.; Schmidt-McCormack, G.R.; Malovic, E.; Mlynarczyk, G.S.A.; Izbicki, P.; Arnold, L.F.; Jefferson, M.A.; de la Rosa, B.M.; Wehrman, R.F.; Luna, K.C.; Hu, H.Z.; Kondru, N.C.; Kleinhenz, M.D.; Smith, J.S.; Manne, S.; Putra, M.R.; Choudhary, S.; Massey, N.; Luo, D.; Berg, C.A.; Acharya, S.; Sharma, S.; Kanuri, S.H.; Lange, J.K.; Carlson, S.A. Off-Target drug effects resulting in altered gene expression events with epigenetic and “Quasi-Epigenetic” origins. Pharmacol. Res., 2016, 107, 229-233.
[] [PMID: 27025785]
Ortinski, P.; Meador, K.J. Cognitive side effects of antiepileptic drugs. Epilepsy Behav., 2004, 5(Suppl. 1), S60-S65.
[] [PMID: 14725848]
Barr, W.B. Understanding the cognitive side effects of antiepileptic drugs: Can functional imaging be helpful? Epilepsy Curr., 2019, 19(1), 22-23.
[] [PMID: 30838926]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy