{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:13:43Z","timestamp":1777497223482,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,6,28]],"date-time":"2018-06-28T00:00:00Z","timestamp":1530144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Pediatrics","award":["E022 Program"],"award-info":[{"award-number":["E022 Program"]}]},{"name":"Military Research Project, Secretar\u00eda de la Defensa Nacional, SEDENA","award":["A022 Program"],"award-info":[{"award-number":["A022 Program"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Epilepsy is a neuronal disease that affects up to 70 million people worldwide. The development of effective therapies to combat childhood epilepsy requires early biomarkers. Here, we performed a whole-genome microarray analysis in blood cells to identify genes differentially expressed between epileptic and epileptic valproic acid (VPA)-treated children versus normal children to obtain information about the gene expression to help us to understand genetic aspects of this disease. We found that the most significant differentially expressed genes were related to the transcriptional factor cAMP-response element binding protein (CREB) that is overexpressed in children with epilepsy compared with normal children, and 6 and 12 months of VPA treatment reversed several of these changes. Interestingly, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), a type I transmembrane glycoprotein that binds collagen proteins and contains CREB binding sites, was one of the more up-regulated genes in epileptic patients, and treatment with VPA strongly reversed its up-regulation. CREB up-regulates genes related to epilepsy; here, we suggest that LAIR1 could activate CREB, and together, they trigger epilepsy. After VPA treatment, LAIR1 repressed genes by disrupting the functional LAIR1\u2013CREB complex, resulting in successful treatment. A functional microarray analysis offers new information that could open novel avenues of research in biomarker discovery, which may be useful for the early identification of children with a predisposition to epilepsy.<\/jats:p>","DOI":"10.3390\/genes9070328","type":"journal-article","created":{"date-parts":[[2018,6,28]],"date-time":"2018-06-28T10:53:33Z","timestamp":1530183213000},"page":"328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Differential Gene Expression Profile Induced by Valproic Acid (VPA) in Pediatric Epileptic Patients"],"prefix":"10.3390","volume":"9","author":[{"given":"Esa\u00fa","family":"Floriano-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Multidisciplinary Research Laboratory, Military Graduate School of Health, SEDENA, 11200 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Brindis","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Laboratory, Military Graduate School of Health, SEDENA, 11200 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7950-4911","authenticated-orcid":false,"given":"Daniel","family":"Ortega-Cuellar","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Nutrition, National Institute of Pediatrics, 04530 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3792-4613","authenticated-orcid":false,"given":"Ivan","family":"Ignacio-Mej\u00eda","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Laboratory, Military Graduate School of Health, SEDENA, 11200 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0160-6429","authenticated-orcid":false,"given":"Elizabeth","family":"Moreno-Arriola","sequence":"additional","affiliation":[{"name":"Genetics Unit of Nutrition, Institute of Biomedical Research UNAM\u2014National Institute of Pediatrics, 04530 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0722-1231","authenticated-orcid":false,"given":"Pablo","family":"Romero-Morelos","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Laboratory, Military Graduate School of Health, SEDENA, 11200 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edgar","family":"Ceballos-Vasquez","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Laboratory, Military Graduate School of Health, SEDENA, 11200 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-3173","authenticated-orcid":false,"given":"Mar\u00eda Guadalupe","family":"C\u00f3rdova-Espinoza","sequence":"additional","affiliation":[{"name":"Multidisciplinary Research Laboratory, Military Graduate School of Health, SEDENA, 11200 Mexico City, Mexico"},{"name":"Bacteriology Medical Laboratory, Microbiology Department, National School of Biological Sciences, National Polytechnic Institute, 11340 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy Karel","family":"Arregoitia-Sarabia","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences, National Institute of Pediatrics, 04530 Mexico City, Mexico"},{"name":"Section of Research and Graduate Studies, National Polytechnic Institute, 11340 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Sandoval-Pacheco","sequence":"additional","affiliation":[{"name":"Military Hospital of Specialties of Women and Neonatology, Service of Emergency, SEDENA, 11200 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liliana","family":"Carmona-Aparicio","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences, National Institute of Pediatrics, 04530 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6580-3440","authenticated-orcid":false,"given":"Noem\u00ed","family":"C\u00e1rdenas-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Laboratory of Neurosciences, National Institute of Pediatrics, 04530 Mexico City, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/WCO.0000000000000174","article-title":"Redefining epilepsy","volume":"28","author":"Fisher","year":"2015","journal-title":"Curr. Opin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.ncl.2016.06.015","article-title":"The epidemiology of global epilepsy","volume":"34","author":"Singh","year":"2016","journal-title":"Neurol. Clin."},{"key":"ref_3","first-page":"186","article-title":"Seizures rate in pediatric outpatients at a ageneral hospital in Mexico City","volume":"65","year":"2008","journal-title":"Bol. Med. Hosp. Infant. Mex."},{"key":"ref_4","first-page":"179","article-title":"Quality of life in adolescent patients with epilepsy in Mexico","volume":"78","author":"Rojas","year":"2010","journal-title":"Rev. Me\u0301d. Hondur."},{"key":"ref_5","first-page":"380","article-title":"Molecular mechanisms mediating involvement of glial cells in brain plastic remodeling in epilepsy","volume":"82","author":"Khaspekov","year":"2017","journal-title":"Biochemistry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.eplepsyres.2017.07.020","article-title":"Altered language network in benign childhood epilepsy patients with spikes from non-dominant side: A resting-state fMRI study","volume":"136","author":"Fang","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.yebeh.2008.09.023","article-title":"Molecular and cellular basis of epileptogenesis in symptomatic epilepsy","volume":"14","author":"Pitkanen","year":"2009","journal-title":"Epilepsy Behav."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.3390\/ijms14011455","article-title":"Role of oxidative stress in refractory epilepsy: Evidence in patients and experimental models","volume":"14","author":"Bandala","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_9","first-page":"759293","article-title":"Relevance of the glutathione system in temporal lobe epilepsy: Evidence in human and experimental models","volume":"2014","author":"Sampieri","year":"2014","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1080\/17512433.2018.1386553","article-title":"A resurging boom in new drugs for epilepsy and brain disorders","volume":"11","author":"Younus","year":"2018","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pohlmann-Eden, B., Marson, A.G., Noack-Rink, M., Ramirez, F., Tofighy, A., Werhahn, K.J., Wild, I., and Trinka, E. (2016). Comparative effectiveness of levetiracetam, valproate and carbamazepine among elderly patients with newly diagnosed epilepsy: Subgroup analysis of the randomized, unblinded KOMET study. BMC Neurol., 16.","DOI":"10.1186\/s12883-016-0663-7"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/1874467210902010095","article-title":"Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection","volume":"2","author":"Monti","year":"2009","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Convertini, P., Shen, M., Xu, X., Lemoine, F., de la Grange, P., Andres, D.A., and Stamm, S. (2013). Valproic acid causes proteasomal degradation of DICER and influences miRNA expression. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082895"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1111\/j.1528-1157.1980.tb04314.x","article-title":"Increase of human plasma GABA by sodium valproate","volume":"21","author":"Loscher","year":"1980","journal-title":"Epilepsia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1212\/WNL.35.5.728","article-title":"Chronic valproic acid therapy and synaptic markers of amino acid neurotransmission","volume":"35","author":"Slevin","year":"1985","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/0924-977X(93)90265-N","article-title":"Effects of valproate on early and late potassium currents of single neurons","volume":"3","author":"Walden","year":"1993","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"738","DOI":"10.4088\/JCP.v65n0601","article-title":"Anticonvulsants as mood stabilizers and adjuncts to antipsychotics: Valproate, lamotrigine, carbamazepine, and oxcarbazepine and actions at voltage-gated sodium channels","volume":"65","author":"Stahl","year":"2004","journal-title":"J. Clin. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0163-7258(02)00299-1","article-title":"Lithium and valproic acid: Parallels and contrasts in diverse signaling contexts","volume":"96","author":"Gurvich","year":"2002","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1016\/j.yexcr.2007.02.019","article-title":"Gadd45a, the gene induced by the mood stabilizer valproic acid, regulates neurite outgrowth through JNK and the substrate paxillin in N1E-115 neuroblastoma cells","volume":"313","author":"Yamauchi","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1399-5618.2004.00164.x","article-title":"Comparative analysis of the effects of four mood stabilizers in SH-SY5Y cells and in primary neurons","volume":"7","author":"Mudge","year":"2005","journal-title":"Bipolar Disord."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S0893-133X(96)00239-4","article-title":"Increase in AP-1 transcription factor DNA binding activity by valproic acid","volume":"16","author":"Chen","year":"1997","journal-title":"Neuropsychopharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.molbrainres.2005.09.002","article-title":"Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway","volume":"142","author":"DeCastro","year":"2005","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1093\/nar\/30.9.e36","article-title":"Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR","volume":"30","author":"Pfaffl","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1023\/B:BILE.0000019559.84305.47","article-title":"Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper-Excel-based tool using pair-wise correlations","volume":"26","author":"Pfaffl","year":"2004","journal-title":"Biotechnol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.nbd.2011.08.009","article-title":"Decreased CREB levels suppress epilepsy","volume":"45","author":"Zhu","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/ncb3158","article-title":"The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development","volume":"17","author":"Kang","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1189\/jlb.0907609","article-title":"The inhibitory collagen receptor LAIR-1 (CD305)","volume":"83","author":"Meyaard","year":"2008","journal-title":"J. Leukoc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S1074-7613(00)80530-0","article-title":"LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes","volume":"7","author":"Meyaard","year":"1997","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E3160","DOI":"10.1073\/pnas.1212753109","article-title":"C1q limits dendritic cell differentiation and activation by engaging LAIR-1","volume":"109","author":"Son","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7975","DOI":"10.1073\/pnas.0913449107","article-title":"Enhanced synaptic connectivity and epilepsy in C1q knockout mice","volume":"107","author":"Chu","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"223","DOI":"10.3892\/etm.2013.1396","article-title":"Effect of topiramate on interleukin 6 expression in the hippocampus of amygdala-kindled epileptic rats","volume":"7","author":"Ye","year":"2014","journal-title":"Exp. Ther. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11612","DOI":"10.1073\/pnas.0813177106","article-title":"Trim24 targets endogenous p53 for degradation","volume":"106","author":"Allton","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12016","DOI":"10.1073\/pnas.0802261105","article-title":"Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration","volume":"105","author":"Balastik","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Naseer, M.I., Chaudhary, A.G., Rasool, M., Kalamegam, G., Ashgan, F.T., Assidi, M., Ahmed, F., Ansari, S.A., Zaidi, S.K., and Jan, M.M. (2016). Copy number variations in Saudi family with intellectual disability and epilepsy. BMC Genom., 17.","DOI":"10.1186\/s12864-016-3091-6"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/bdra.23458","article-title":"Array-based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions","volume":"106","author":"Krutzke","year":"2016","journal-title":"Birth Defects Res. A Clin. Mol. Teratol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/cne.20729","article-title":"Constitutive neuronal expression of CCR2 chemokine receptor and its colocalization with neurotransmitters in normal rat brain: Functional effect of MCP-1\/CCL2 on calcium mobilization in primary cultured neurons","volume":"492","author":"Banisadr","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7878","DOI":"10.1523\/JNEUROSCI.0315-17.2017","article-title":"Chemokine CCL2-CCR2 signaling induces neuronal cell death via STAT3 activation and IL-1\u03b2 production after status epilepticus","volume":"37","author":"Tian","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1093\/hmg\/6.8.1225","article-title":"Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell\u2019s waltzer mice","volume":"6","author":"Avraham","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s12035-009-8072-1","article-title":"Inducible cAMP early repressor (ICER) and brain functions","volume":"40","author":"Borlikova","year":"2009","journal-title":"Mol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.neuroscience.2007.10.064","article-title":"The role of transcription factors cyclic-AMP responsive element modulator (CREM) and inducible cyclic-AMP early repressor (ICER) in epileptogenesis","volume":"152","author":"Porter","year":"2008","journal-title":"Neuroscience"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/9\/7\/328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:10:36Z","timestamp":1760195436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/9\/7\/328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,28]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["genes9070328"],"URL":"https:\/\/doi.org\/10.3390\/genes9070328","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,28]]}}}