Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Phiel et al. (174), using cell lines, showed that valproate at therapeutic concentrations inhibits histone deacetylases; this inhibition correlates with increased expression of multiple genes.
“Phiel et al. (174), using cell lines, showed that valproate at therapeutic concentrations inhibits histone deacetylases; this inhibition correlates with increased expression of multiple genes.”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [174]
Valproic acid is known as a reactivator of silenced genes and appeared to be a weak reactivator of full mutation.
“The third tested compound is valproic acid (101), which is already known as a reactivator of silenced genes (102) that appeared to be a weak reactivator of FM (103).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Schreiber, E. H., Matthias, P., Müller, M. M., & Schaffner, W. (1989) · Nucleic Acids Research · doi:10.1093/nar/17.15.6419 · Cited by 4,179 · see citing works
Constitutive Transcriptional Activation by a β-Catenin-Tcf Complex in APC −/− Colon Carcinoma
Kořínek, V., Barker, N., Morin, P. J., van Wichen, D. F., de Weger, R. A., Kinzler, K. W., Vogelstein, B., & Clevers, H. C. (1997) · Science · doi:10.1126/science.275.5307.1784 · Cited by 3,304 · see citing works
A molecular mechanism for the effect of lithium on development.
Klein, P. S., & Melton, D. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8455 · Cited by 2,305 · see citing works
Self-citationLithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells
Stambolic, V., Ruel, L., & Woodgett, J. R. (1996) · Current Biology · doi:10.1016/s0960-9822(02)70790-2 · Cited by 1,321 · see citing works
Hallcher, L. M., & Sherman, W. R. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)70391-3 · Cited by 1,102 · see citing works
Richon, V. M., Sandhoff, T. W., Rifkind, R. A., & Marks, P. A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.180316197 · Cited by 1,090 · see citing works
Neural and developmental actions of lithium: A unifying hypothesis
Berridge, M. J., Downes, C. P., & Hanley, M. R. (1989) · Cell · doi:10.1016/0092-8674(89)90026-3 · Cited by 1,016 · see citing works
What's Up and Down with Histone Deacetylation and Transcription?
Pazin, M. J., & Kadonaga, J. T. (1997) · Cell · doi:10.1016/s0092-8674(00)80211-1 · Cited by 820 · see citing works
Deacetylation of p53 modulates its effect on cell growth and apoptosis
Luo, J., Su, F., Chen, D., Shiloh, A., & Gu, W. J. (2000) · Nature · doi:10.1038/35042612 · Cited by 818 · see citing works
Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways
Miller, J. R., Hocking, A. M., Brown, J. D., & Moon, R. T. (1999) · Oncogene · doi:10.1038/sj.onc.1203245 · Cited by 689 · see citing works
(1996) · Europe PMC (PubMed Central) · Cited by 659 · see citing works
Activation of the Wnt Signaling Pathway: A Molecular Mechanism for Lithium Action
Hedgepeth, C. M., Conrad, L. J., Zhang, J., Huang, H., Lee, V. M.-Y., & Klein, P. S. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8552 · Cited by 637 · see citing works
Self-citationLint, C. M. V., Emiliani, S., Ott, M., & Verdin, E. M. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00449.x · Cited by 579 · see citing works
HDAC4 deacetylase associates with and represses the MEF2 transcription factor
Miska, E. A., Karlsson, C., Langley, E., Nielsen, S. J., Pines, J., & Kouzarides, T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.18.5099 · Cited by 551 · see citing works
MATERNAL VALPROIC ACID AND CONGENITAL NEURAL TUBE DEFECTS
Robert, E., & Guibaud, P. (1982) · The Lancet · doi:10.1016/s0140-6736(82)90908-4 · Cited by 545 · see citing works
Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau.
Greenberg, S. G., Davies, P., Schein, J., & Binder, L. I. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)48531-6 · Cited by 542 · see citing works
Molecular Targets of Lithium Action
Phiel, C. J., & Klein, P. S. (2001) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.41.1.789 · Cited by 513 · see citing works
Self-citationThe Mood‐Stabilizing Agent Valproate Inhibits the Activity of Glycogen Synthase Kinase‐3
Chen, G., Huang, L., Jiang, Y., & Manji, H. K. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0721327.x · Cited by 439 · see citing works
Yang, W., Yao, Y., Sun, J.-M., Davie, J., & Seto, E. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.44.28001 · Cited by 433 · see citing works
Nonaka, S., Hough, C. J., & Chuang, D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2642 · Cited by 430 · see citing works
Mechanisms of action of valproate: a commentatory
Johannessen, C. (2000) · Neurochemistry International · doi:10.1016/s0197-0186(00)00013-9 · Cited by 400 · see citing works
Sambucetti, L. C., Fischer, D. D., Zabludoff, S., Kwon, P. O., Chamberlin, H., Trogani, N., Xu, H. W., & Cohen, D. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.49.34940 · Cited by 390 · see citing works
Huang, E. Y., Zhang, J., Miska, E. A., Guenther, M. G., Kouzarides, T., & Lazar, M. A. (2000) · Genes & Development · doi:10.1101/gad.14.1.45 · Cited by 325 · see citing works
Self-citationNau, H., Hauck, R.-S., & Ehlers, K. (1991) · Pharmacology & Toxicology · doi:10.1111/j.1600-0773.1991.tb01303.x · Cited by 301 · see citing works
Wt, W. (1984) · PubMed · Cited by 289 · see citing works
David, G., Alland, L., Hong, S.-H., Wong, C.-W., DePinho, R. A., & Dejean, A. (1998) · Oncogene · doi:10.1038/sj.onc.1202043 · Cited by 281 · see citing works
[Pharmacodynamic properties of N-dipropylacetic acid].
Meunier, H., Carraz, G., Neunier, Y., et al. (1998) · PubMed · Cited by 250 · see citing works
Evidence for a mitogenic effect of Wnt-1 in the developing mammalian central nervous system
Dickinson, M. E., Krumlauf, R. K., & McMahon, A. P. (1994) · Development · doi:10.1242/dev.120.6.1453 · Cited by 243 · see citing works
Manji, H. K., & Lenox, R. H. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00235-8 · Cited by 241 · see citing works
Thomas, G. M., Frame, S., Goedert, M., Näthke, I. S., Polakis, P. G., & Cohen, P. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01161-8 · Cited by 229 · see citing works
Billin, A. N., Thirlwell, H., & Ayer, D. E. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.18.6882-6890.2000 · Cited by 216 · see citing works
Cloning and characterization of a novel human histone deacetylase, HDAC8
BUGGY, J. J., SIDERIS, M. L., MAK, P., LORIMER, D. D., MCINTOSH, B., & CLARK, J. M. (2000) · Biochemical Journal · doi:10.1042/bj3500199 · Cited by 197 · see citing works
A CBP/p300 homolog specifies multiple differentiation pathways in Caenorhabditis elegansPreprint
Shi, Y., & Mello, C. C. (1998) · Genes & Development · doi:10.1101/gad.12.7.943 · Cited by 166 · see citing works
York, J. D., Ponder, J. W., & Majerus, P. W. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.5149 · Cited by 159 · see citing works
NURD-complex genes antagonise Ras-induced vulval development in Caenorhabditis elegans
Solari, F., & Ahringer, J. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00343-2 · Cited by 153 · see citing works
Histone deacetylase inhibitors as potential anti-skin cancer agents.
Saunders, N. A., Dicker, T., Popa, C., Jones, S. J. M., & Dahler, A. L. (1999) · PubMed · Cited by 137 · see citing works
Vaden, D. L., Ding, D., Peterson, B. C., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m004179200 · Cited by 131 · see citing works
Nonaka, S., Katsube, N. C., & Chuang, D.-M. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37615-3 · Cited by 131 · see citing works
Histone Acetylation Influences both Gene Expression and Development of Xenopus laevis
Almouzni, G., Khochbin, S., Dimitrov, S. I., & Wolffe, A. P. (1994) · Developmental Biology · doi:10.1006/dbio.1994.1283 · Cited by 130 · see citing works
Neurobiology of lithium: an update.
Lenox, R. H., McNamara, R. K., Papke, R. L., & Manji, H. K. (1998) · PubMed · Cited by 125 · see citing works
Mechanisms of action of antiepileptic drugs
Davies, J. A. (1995) · Seizure · doi:10.1016/s1059-1311(95)80003-4 · Cited by 117 · see citing works
The Rpd3 histone deacetylase is required for segmentation of the Drosophila embryo
Mannervik, M., & Levine, M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.12.6797 · Cited by 113 · see citing works
Huang, H., Reed, C. P., Zhang, J. S., Shridhar, V., Wang, L., & Smith, D. I. (1999) · PubMed · Cited by 111 · see citing works
Different mechanisms of protection against apoptosis by valproate and Li+
Mora, A., González‐Polo, R. A., Fuentes, J. M., Soler, G., & Centeno, F. (1999) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.1999.00919.x · Cited by 101 · see citing works
Valproate robustly enhances AP-1 mediated gene expression
Chen, G., Yuan, P.-X., Jiang, Y., Huang, L., & Manji, H. K. (1999) · Molecular Brain Research · doi:10.1016/s0169-328x(98)00303-9 · Cited by 101 · see citing works
Svensson, K., Mattsson, R., James, T. C., Wentzel, P., Pilartz, M., MacLaughlin, J., Miller, S. J., Olsson, T., Eriksson, U. J., & OHLSSON, R. I. (1998) · Development · doi:10.1242/dev.125.1.61 · Cited by 101 · see citing works
Wang, J., Bown, C. D., & Young, L. T. (1999) · Molecular Pharmacology · doi:10.1016/s0026-895x(24)12177-3 · Cited by 96 · see citing works
Fredieu, J. R., Cui, Y., Maier, D., Danilchik, M. V., & Christian, J. L. (1997) · Developmental Biology · doi:10.1006/dbio.1997.8566 · Cited by 87 · see citing works
Bordonaro, M., Mariadason, J. M., Aslam, F., et al. (1999) · PubMed · Cited by 87 · see citing works
Asghari, V., Wang, J. F., Reiach, J. S., et al. (1998) · Molecular Brain Research · doi:10.1016/s0169-328x(98)00107-7 · Cited by 83 · see citing works
Dixon, J. F., & Hokin, L. E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4757 · Cited by 77 · see citing works
Staal, F. J. T., Burgering, B. M. T., van de Wetering, M., & Clevers, H. C. (1999) · International Immunology · doi:10.1093/intimm/11.3.317 · Cited by 75 · see citing works
Murray, M., & Greenberg, M. L. (2000) · Molecular Microbiology · doi:10.1046/j.1365-2958.2000.01886.x · Cited by 72 · see citing works
Strain differences in the teratogenicity induced by sodium valproate in cultured mouse embryos
Naruse, I., Collins, M. D., & Scott, W. J. (1988) · Teratology · doi:10.1002/tera.1420380113 · Cited by 66 · see citing works
Myo-Inositol Monophosphatase: Diverse Effects of Lithium, Carbamazepine, and Valproate
Vadnal, R. E. (1995) · Neuropsychopharmacology · doi:10.1016/0893-133x(94)00088-h · Cited by 61 · see citing works
Manji, H. K., McNamara, R. K., Chen, G., & Lenox, R. H. (1999) · Australian & New Zealand Journal of Psychiatry · doi:10.1111/j.1440-1614.1999.00670.x · Cited by 60 · see citing works
Lampen, A., Siehler, S., Ellerbeck, U., Göttlicher, M., & Nau, H. (1999) · Toxicology and Applied Pharmacology · doi:10.1006/taap.1999.8770 · Cited by 60 · see citing works
Actions of sodium valproate on the central nervous system.
Tunnicliff, G. (1999) · PubMed · Cited by 59 · see citing works
Valproic acid for the treatment of pediatric malignant glioma
Driever, P. H., Knüpfer, M. M., Cinatl, J. J., & Wolff, J. E. A. (1999) · Klinische Pädiatrie · doi:10.1055/s-2008-1043809 · Cited by 55 · see citing works
Microtubule‐associated Protein Tau, Paired Helical Filaments, and Phosphorylationa
Mandelkow, E., BIERNAT, J., DREWES, G., STEINER, B., LICHTENBERG‐KRAAG, B., WILLE, H., GUSTKE, N., & MANDELKOW, E. (1993) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1993.tb23054.x · Cited by 53 · see citing works
Inokoshi, J., Katagiri, M., Arima, S., Tanaka, H., Hayashi, M., Kim, Y. B., Furumai, R., Yoshida, M., Horinouchi, S., & Ōmura, S. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0316 · Cited by 50 · see citing works
Dawson, D. A. (1991) · Teratology · doi:10.1002/tera.1420440507 · Cited by 48 · see citing works
The Use of Valproic Acid in HIV-Positive Patients
Jennings, H. R., & Romanelli, F. (1999) · Annals of Pharmacotherapy · doi:10.1345/aph.19014 · Cited by 47 · see citing works
Characterization of a Bioengineered Chimeric Na+-Nucleoside Transporter
Wang, J., & Giacomini, K. M. (1999) · Molecular Pharmacology · doi:10.1124/mol.55.2.234 · Cited by 31 · see citing works
In vivo uptake of valproic acid into brain
Hammond, E. J., Perchalski, R. J., Villarreal, H. J., et al. (1982) · Brain Research · doi:10.1016/0006-8993(82)90664-3 · Cited by 20 · see citing works
Kinoshita, K., & Asashima, M. (1995) · Development · doi:10.1242/dev.121.6.1581 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- Dixon, J. F., and Hokin, L. E. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 4757-4760
- Nonaka, S., Hough, C. J., and Chuang, D. M. (1998) Proc. Natl. Acad. Sci.
- York, J. D., Ponder, J. W., and Majerus, P. W. (1995) Proc. Natl. Acad. Sci.
- Klein, P. S., and Melton, D. A. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 8455-8459
- Mannervik, M., and Levine, M. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 6797-6801
- Saunders, N., Dicker, A., Popa, C., Jones, S., and Dahler, A. (1999) Cancer Res. 59, 399 -404
- Richon, V. M., Sandhoff, T. W., Rifkind, R. A., and Marks, P. A. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 10014 -10019
Cited by
Sorted by citations
Combination therapy in combating cancer
Mokhtari, R. B., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., & Yeger, H. (2017) · Oncotarget · doi:10.18632/oncotarget.16723 · Cited by 2,543 · see citing works
Histone deacetylases and cancer: causes and therapies
Marks, P. A., Rifkind, R. A., Richon, V. M., Breslow, R., Miller, T., & Kelly, W. K. (2001) · Nature reviews. Cancer · doi:10.1038/35106079 · Cited by 1,866 · see citing works
Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor
Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., Grueter, C. A., Lim, H., Saunders, L. R., Stevens, R. D., et al. (2013) · Science · doi:10.1126/science.1227166 · Cited by 1,777 · see citing works
Phenotypic plasticity and the epigenetics of human disease
Feinberg, A. P. (2007) · Nature · doi:10.1038/nature05919 · Cited by 1,613 · see citing works
Histone-deacetylase inhibitors: novel drugs for the treatment of cancer
Johnstone, R. W. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd772 · Cited by 1,515 · see citing works
Haggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M., & Schreiber, S. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0430973100 · Cited by 1,066 · see citing works
Multiple roles of HDAC inhibition in neurodegenerative conditions
Chuang, D.-M., Leng, Y., Marinova, Z., Kim, H.-J., & Chiu, C.-T. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.06.002 · Cited by 676 · see citing works
Reelin promoter hypermethylation in schizophrenia
Grayson, D. R., Jia, X., Chen, Y., Sharma, R. P., Mitchell, C. P., Guidotti, A., & Costa, E. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503736102 · Cited by 553 · see citing works
The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2
Krämer, O. H., Zhu, P., Ostendorff, H. P., Golebiewski, M., Tiefenbach, J., Peters, M. A., Brill, B., Groner, B., Bach, I., Heinzel, T., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg315 · Cited by 523 · see citing works
Valproic acid in pregnancy: how much are we endangering the embryo and fetus?
Ornoy, A. (2009) · Reproductive Toxicology · doi:10.1016/j.reprotox.2009.02.014 · Cited by 526 · see citing works
Characteristics of fetal anticonvulsant syndrome associated autistic disorder
Rasalam, A., Hailey, H., Williams, J., Moore, S., Turnpenny, P., Lloyd, D., & Dean, J. (2005) · Developmental Medicine & Child Neurology · doi:10.1017/s0012162205001076 · Cited by 456 · see citing works
Therapeutic potential of mood stabilizers lithium and valproic acid:Beyond bipolar disorder
Chiu, C.-T., Wang, Z., Hunsberger, J. G., & Chuang, D.-M. (2013) · Pharmacological Reviews · doi:10.1124/pr.111.005512 · Cited by 404 · see citing works
Yasuda, S., Liang, M.-H., Marinova, Z., Yahyavi, A., & Chuang, D.-M. (2009) · Molecular Psychiatry · doi:10.1038/sj.mp.4002099 · Cited by 358 · see citing works
Kataoka, S., Takuma, K., Hara, Y., Maeda, Y., Ago, Y., & Matsuda, T. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001714 · Cited by 341 · see citing works
Valproate Induces Replication-independent Active DNA Demethylation
Detich, N., Bovenzi, V., & Szyf, M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303740200 · Cited by 345 · see citing works
Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics
Bagni, C., Tassone, F., Neri, G., & Hagerman, R. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63141 · Cited by 321 · see citing works
Johannessen Landmark, C. (2008) · CNS Drugs · doi:10.2165/00023210-200822010-00003 · Cited by 316 · see citing works
Regulation of Ketone Body Metabolism and the Role of PPARα
Grabacka, M., Pierzchalska, M., Dean, M., & Reiss, K. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17122093 · Cited by 305 · see citing works
Is Glycogen Synthase Kinase-3 a Central Modulator in Mood Regulation?
Li, X., & Jope, R. S. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.105 · Cited by 294 · see citing works
Nankova, B. B., Agarwal, R., MacFabe, D. F., & La Gamma, E. F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103740 · Cited by 294 · see citing works
Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms
Tordjman, S., Somogyi, E., Coulon, N., Kermarrec, S., Cohen, D., Bronsard, G., Bonnot, O., Weismann-Arcache, C., Botbol, M., Lauth, B., et al. (2014) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2014.00053 · Cited by 283 · see citing works
Chen, P. S., Wang, C.-C., Bortner, C. D., Peng, G.-S., Wu, X., Pang, H., Lu, R.-B., Gean, P.-W., Chuang, D.-M., & Hong, J.-S. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.06.053 · Cited by 262 · see citing works
Valproate Induces widespread epigenetic reprogramming which involves demethylation of specific genes
Milutinovic, S., D'Alessio, A. C., Detich, N., & Szyf, M. (2007) · Carcinogenesis · doi:10.1093/carcin/bgl167 · Cited by 256 · see citing works
Autism Spectrum Disorders and Epigenetics
Grafodatskaya, D., Chung, B., Szatmari, P., & Weksberg, R. (2010) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1016/j.jaac.2010.05.005 · Cited by 235 · see citing works
Programming Bugs: Microbiota and the Developmental Origins of Brain Health and Disease
Codagnone, M. G., Spichak, S., O’Mahony, S. M., O’Leary, O. F., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.06.014 · Cited by 198 · see citing works
Altered gene expression of histone deacetylases in mood disorder patients
Hobara, T., Uchida, S., Otsuki, K., Matsubara, T., Funato, H., Matsuo, K., Suetsugi, M., & Watanabe, Y. (2010) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2009.08.015 · Cited by 185 · see citing works
Is there a future for histone deacetylase inhibitors in the pharmacotherapy of psychiatric disorders
Grayson, D. R., Kundakovic, M., & Sharma, R. P. (2010) · Molecular Pharmacology · doi:10.1124/mol.109.061333 · Cited by 171 · see citing works
Valproate reopens critical-period learning of absolute pitch
Gervain, J., Vines, B. W., Chen, L. M., Seo, R. J., Hensch, T. K., Werker, J. F., & Young, A. H. (2013) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2013.00102 · Cited by 151 · see citing works
DeCastro, M., Nankova, B. B., Shah, P., Patel, P., Mally, P. V., Mishra, R., & La Gamma, E. F. (2005) · Molecular Brain Research · doi:10.1016/j.molbrainres.2005.09.002 · Cited by 149 · see citing works
Establishment of intestinal organoid cultures modeling injury-associated epithelial regeneration
Qu, M., Xiong, L., Lyu, Y., Zhang, X., Shen, J., Guan, J., Chai, P., Lin, Z., Nie, B., Li, C., et al. (2021) · Cell Research · doi:10.1038/s41422-020-00453-x · Cited by 138 · see citing works
Antiepileptic drugs and pregnancy outcomes
Wlodarczyk, B. J., Palacios, A. M., George, T. M., & Finnell, R. H. (2012) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.35438 · Cited by 138 · see citing works
Raffoux, E., Cras, A., Recher, C., Boëlle, P.-Y., de Labarthe, A., Turlure, P., Marolleau, J.-P., Reman, O., Gardin, C., Victor, M., et al. (2010) · Oncotarget · doi:10.18632/oncotarget.106 · Cited by 134 · see citing works
Venkataramani, V., Rossner, C., Iffland, L., Schweyer, S., Tamboli, I. Y., Walter, J., Wirths, O., & Bayer, T. A. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.057836 · Cited by 133 · see citing works
Epigenetics of drug abuse: predisposition or response
Nielsen, D. A., Utrankar, A., Reyes, J. A., Simons, D. D., & Kosten, T. R. (2012) · Pharmacogenomics · doi:10.2217/pgs.12.94 · Cited by 125 · see citing works
Antiepileptic drugs and the developing brain
Kaindl, A. M., Asimiadou, S., Manthey, D., Hagen, M. V. D., Turski, L., & Ikonomidou, C. (2006) · Cellular and Molecular Life Sciences CMLS · doi:10.1007/s00018-005-5348-0 · Cited by 121 · see citing works
Protection of dopaminergic cells from MPP+-mediated toxicity by histone deacetylase inhibition
Kidd, S. K., & Schneider, J. S. (2010) · Brain Research · doi:10.1016/j.brainres.2010.07.041 · Cited by 113 · see citing works
Gomes, F. V., Zhu, X., & Grace, A. A. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0514-1 · Cited by 91 · see citing works
Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications
Szyf, M. (2015) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2014.01.009 · Cited by 76 · see citing works
Krystal, J. H., Tolin, D. F., Sanacora, G., Castner, S. A., Williams, G. V., Aikins, D. E., Hoffman, R. E., & D'Souza, D. C. (2009) · Drug Discovery Today · doi:10.1016/j.drudis.2009.05.002 · Cited by 76 · see citing works
Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys
Torrioli, M., Vernacotola, S., Setini, C., Bevilacqua, F., Martinelli, D., Snape, M., Hutchison, J. A., Di Raimo, F. R., Tabolacci, E., & Neri, G. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33484 · Cited by 71 · see citing works
Yoo, D. Y., Kim, W., Nam, S. M., Kim, D. W., Chung, J. Y., Choi, S. Y., Yoon, Y. S., Won, M.-H., & Hwang, I. K. (2011) · Neurochemical Research · doi:10.1007/s11064-011-0503-5 · Cited by 60 · see citing works
Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors
Halsall, J., Gupta, V., O'Neill, L. P., Turner, B. M., & Nightingale, K. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033453 · Cited by 57 · see citing works
“Valproic acid (VPA) is a branched short-chain fatty acid HDAC inhibitor (HDACi) that is used clinically as a preventive treatment for seizures and bipolar disorder [7].”
BackgroundValproic acid induces microglial dysfunction, not apoptosis, in human glial cultures
Gibbons, H. M., Smith, A. M., Teoh, H. H., Bergin, P. M., Mee, E. W., Faull, R. L. M., & Dragunow, M. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.08.024 · Cited by 49 · see citing works
Sabers, A., Bertelsen, F. C. B., Scheel-Krüger, J., Nyengaard, J. R., & Møller, A. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.07.036 · Cited by 43 · see citing works
Tabolacci, E., De Pascalis, I., Accadia, M., Terracciano, A., Moscato, U., Chiurazzi, P., & Neri, G. (2008) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32830500a1 · Cited by 44 · see citing works
Environmental epigenomics: understanding the effects of parental care on the epigenome
McGowan, P. O., & Szyf, M. (2010) · Essays in Biochemistry · doi:10.1042/bse0480275 · Cited by 39 · see citing works
Association of DNA Methylation with Acute Mania and Inflammatory Markers
Sabunciyan, S., Maher, B., Bahn, S., Dickerson, F., & Yolken, R. H. (2015) · PLOS ONE · doi:10.1371/journal.pone.0132001 · Cited by 35 · see citing works
Ribeiro, A. C. R., Jahr, F. M., Hawkins, E., Kronfol, M. M., Younis, R. M., McClay, J. L., & Deshpande, L. S. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119765 · Cited by 30 · see citing works
- Authors
- Phiel, C. J., Zhang, F., Huang, E. Y., Guenther, M. G., Lazar, M. A., & Klein, P. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-09
- Volume
- 276
- Issue
- 39
- Pages
- 36734-36741
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2098249941
- Cited by
- 1,758
- References
- 67
- Citations by year
- 2026: 32 · 2025: 50 · 2024: 39 · 2023: 46 · 2022: 65 · 2021: 78 · 2020: 77 · 2019: 53 · 2018: 56 · 2017: 66 · 2016: 93 · 2015: 90 · 2014: 102 · 2013: 110 · 2012: 93
- FWCI
- 13.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (DK43806)
- National Institute of Mental Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK43806, R01DK045586, DK 45586)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- valproic acid, histone deacetylase inhibition, HDAC1, trichostatin A, histone hyperacetylation, lithium, bipolar disorder, epilepsy, teratogenicity, congenital malformations, antiepileptic drugs, mood stabilizers, transcriptional activation
- MeSH terms
- Acetylation, Animals, Anticonvulsants, Cell Line, Dose-Response Relationship, Drug, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Lithium, Luminescent Proteins, Plasmids, Promoter Regions, Genetic, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Teratogens, Time Factors, Transcription, Genetic, Transfection, Valproic Acid, Xenopus, Signal Transduction, Calcium-Calmodulin-Dependent Protein Kinases, Antimanic Agents, Inhibitory Concentration 50, Zebrafish Proteins, Glycogen Synthase Kinase 3, Green Fluorescent Proteins, Wnt Proteins, Histone Deacetylase 1, Histone Deacetylase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review