{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:51:40Z","timestamp":1787003500499,"version":"build-2736575974"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T00:00:00Z","timestamp":1510185600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T00:00:00Z","timestamp":1510185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Many neurological disorders of gluten-related diseases (GRD), not directly referable to the gastrointestinal tract, have been reported in association with celiac disease (CD), including ataxia, neuropathy and epilepsy. In particular, people with epilepsy diagnosed with CD seems to be characterized by intractable seizure. In these patients, gluten restriction diet has resulted in a reduction of both seizure frequency and antiepileptic medication. Many hypotheses have been suggested, however, molecular mechanisms that associates GRD and epileptogenesis are yet unknown. In this study, we examined the effects of the toxic gliadin peptide 31-43 in\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    models of kainate-induced-epilepsy. We observed that p31-43 exacerbates kainate neurotoxicity in epilepsy models, through the involvement of the enzymatic activity of transglutaminases. Moreover, electrophysiological recordings in CA3 pyramidal neurons of organotypic hippocampal slices show that p31-43 increases the inward current induced by kainate, the average sEPSC amplitude and the total number of evoked action potentials when applicated alone, thus suggesting that p31-43 is able to influence CA3-CA1 neurotransmission and can potentiate postsynaptic kainate receptors. Our results suggest a possible mechanism underlying the relationship between GRD and epilepsy through a potentiation of kainate-induced neurotoxicity and links the toxic effects of gluten to epilepsy.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-14845-4","type":"journal-article","created":{"date-parts":[[2017,11,3]],"date-time":"2017-11-03T10:25:14Z","timestamp":1509704714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The gliadin peptide 31-43 exacerbates kainate neurotoxicity in epilepsy models"],"prefix":"10.1038","volume":"7","author":[{"given":"Elisabetta","family":"Gerace","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Resta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Landucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Renzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Masi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico E.","family":"Pellegrini-Giampietro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Calabr\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8273-7377","authenticated-orcid":false,"given":"Guido","family":"Mannaioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,9]]},"reference":[{"issue":"1","key":"14845_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s11126-011-9186-y","volume":"83","author":"JR Jackson","year":"2012","unstructured":"Jackson, J. R., Eaton, W. W., Cascella, N. G., Fasano, A. & Kelly, D. L. Neurologic and psychiatric manifestations of celiac disease and gluten sensitivity. Psychiatr Q. \n                           83(1), 91\u2013102 (2012).","journal-title":"Psychiatr Q."},{"issue":"1-2","key":"14845_CR2","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.jneuroim.2008.01.008","volume":"195","author":"C Briani","year":"2008","unstructured":"Briani, C. et al. Neurological complications of celiac disease and autoimmune mechanisms: a prospective study. J. Neuroimmunol. \n                           195(1-2), 171\u20135 (2008).","journal-title":"J. Neuroimmunol."},{"issue":"9140","key":"14845_CR3","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1016\/S0140-6736(98)05342-2","volume":"352","author":"M Hadjivassiliou","year":"1998","unstructured":"Hadjivassiliou, M. et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet. \n                           352(9140), 1582\u20135 (1998).","journal-title":"Lancet."},{"issue":"4","key":"14845_CR4","doi-asserted-by":"publisher","first-page":"751","DOI":"10.17219\/acem\/43585","volume":"25","author":"H Bashiri","year":"2016","unstructured":"Bashiri, H., Afshari, D., Babaei, N. & Ghadami, M. R. Celiac Disease and Epilepsy: The Effect of Gluten-Free Diet on Seizure Control. Adv Clin. Exp. Med. \n                           25(4), 751\u20134 (2016).","journal-title":"Adv Clin. Exp. Med."},{"issue":"3","key":"14845_CR5","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.pediatrneurol.2006.11.011","volume":"36","author":"A Mavroudi","year":"2007","unstructured":"Mavroudi, A. et al. Increased prevalence of silent celiac disease among Greek epileptic children. Pediatr, Neurol. \n                           36(3), 165\u20139 (2007).","journal-title":"Pediatr, Neurol."},{"issue":"6","key":"14845_CR6","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1136\/jnnp.2008.148221","volume":"80","author":"M Peltola","year":"2009","unstructured":"Peltola, M. et al. Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity. J Neurol. Neurosurg. Psychiatry. \n                           80(6), 626\u201330 (2009).","journal-title":"J Neurol. Neurosurg. Psychiatry."},{"issue":"921","key":"14845_CR7","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1136\/pmj.78.921.393","volume":"78","author":"DS Pengiran Tengah","year":"2002","unstructured":"Pengiran Tengah, D. S., Wills, A. J. & Holmes, G. K. Neurological complications of coeliac disease. Postgrad. Med. J. \n                           78(921), 393\u20138 (2002).","journal-title":"Postgrad. Med. J."},{"issue":"4","key":"14845_CR8","doi-asserted-by":"publisher","first-page":"278","DOI":"10.2174\/187152812800959004","volume":"11","author":"A Martin","year":"2012","unstructured":"Martin, A. et al. Pathophysiological roles of transglutaminase - catalyzed reactions in the pathogenesis of human diseases. Inflamm. Allergy Drug Targets. \n                           11(4), 278\u201384 (2012).","journal-title":"Inflamm. Allergy Drug Targets."},{"issue":"10","key":"14845_CR9","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1016\/j.autrev.2012.01.007","volume":"11","author":"A Di Sabatino","year":"2012","unstructured":"Di Sabatino, A. et al. The function of tissue transglutaminase in celiac disease. Autoimmun. Rev. \n                           11(10), 746\u201353 (2012).","journal-title":"Autoimmun. Rev."},{"issue":"4","key":"14845_CR10","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/ajg.2015.434","volume":"111","author":"M Hadjivassiliou","year":"2016","unstructured":"Hadjivassiliou, M. et al. Neurological Dysfunction in Coeliac Disease and Non-Coeliac Gluten Sensitivity. Am. J. Gastroenterol. \n                           111(4), 561\u20137 (2016).","journal-title":"Am. J. Gastroenterol."},{"key":"14845_CR11","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1002\/ana.21450","volume":"64","author":"M Hadjivassiliou","year":"2008","unstructured":"Hadjivassiliou, M. et al. Autoantibodies in Gluten Ataxia Recognize a Novel Neuronal Transglutaminase. Ann. Neurol. \n                           64, 332\u2013343 (2008).","journal-title":"Ann. Neurol."},{"issue":"19","key":"14845_CR12","doi-asserted-by":"publisher","first-page":"1740","DOI":"10.1212\/WNL.0b013e3182919070","volume":"80","author":"M Hadjivassiliou","year":"2013","unstructured":"Hadjivassiliou, M. et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology. \n                           80(19), 1740\u20135 (2013).","journal-title":"Neurology."},{"issue":"5590","key":"14845_CR13","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1126\/science.1074129","volume":"297","author":"L Shan","year":"2002","unstructured":"Shan, L. et al. Structural basis for gluten intolerance in celiac sprue. Science. \n                           297(5590), 2275\u20139 (2002).","journal-title":"Science."},{"key":"14845_CR14","doi-asserted-by":"publisher","first-page":"247","DOI":"10.3109\/00365529609004874","volume":"31","author":"L Maiuri","year":"1996","unstructured":"Maiuri, L. et al. In vitro activities of A-gliadin synthetic peptides: damaging effect on the atrophic coeliac mucosa and activation of mucosal immune response in the treated coeliac mucosa. Scand. J. Gastroenterol. \n                           31, 247\u2013253 (1996).","journal-title":"Scand. J. Gastroenterol."},{"issue":"6","key":"14845_CR15","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1159\/000016887","volume":"16","author":"PJ Ciclitira","year":"1998","unstructured":"Ciclitira, P. J. & Ellis, H. J. In vivo gluten ingestion in coeliac disease. Dig. Dis. \n                           16(6), 337\u201340 (1998).","journal-title":"Dig. Dis."},{"issue":"9377","key":"14845_CR16","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/S0140-6736(03)13803-2","volume":"362","author":"L Maiuri","year":"2003","unstructured":"Maiuri, L. et al. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet. \n                           362(9377), 30\u20137 (2003).","journal-title":"Lancet."},{"issue":"1","key":"14845_CR17","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/2045-8118-10-11","volume":"10","author":"M Morin-Brureau","year":"2013","unstructured":"Morin-Brureau, M., De Bock, F. & Lerner-Natoli, M. Organotypic brain slices: a model to study the neurovascular unit micro-environment in epilepsies. Fluids Barriers CNS. \n                           10(1), 11 (2013).","journal-title":"Fluids Barriers CNS."},{"key":"14845_CR18","doi-asserted-by":"crossref","unstructured":"Chapman, R.W., Laidlow, J. M., Colin-Jones, D., Eade, O. E., Smith, C. L. Increased prevalence of epilepsy in coeliac disease. Br. Med J. 22; 2(6132):250-1 (1978).","DOI":"10.1136\/bmj.2.6132.250"},{"issue":"8817","key":"14845_CR19","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/0140-6736(92)91766-2","volume":"340","author":"G Gobbi","year":"1992","unstructured":"Gobbi, G. et al. Coeliac disease, epilepsy, and cerebral calcifications. The Italian Working Group on Coeliac Disease and Epilepsy. Lancet. \n                           340(8817), 439\u201343 (1992).","journal-title":"Lancet."},{"issue":"1","key":"14845_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuint.2004.01.005","volume":"45","author":"IE Holopainen","year":"2004","unstructured":"Holopainen, I. E., J\u00e4rvel\u00e4, J., Lopez-Picon, F. R., Pelliniemi, L. J. & Kukko-Lukjanov, T. K. Mechanisms of kainate-induced region-specific neuronal death in immature organotypic hippocampal slice cultures. Neurochem Int. \n                           45(1), 1\u201310 (2004).","journal-title":"Neurochem Int."},{"issue":"9","key":"14845_CR21","doi-asserted-by":"publisher","first-page":"e108228","DOI":"10.1371\/journal.pone.0108228","volume":"9","author":"YC Huang","year":"2014","unstructured":"Huang, Y. C. et al. Transglutaminase 2 expression is increased as a function of malignancy grade and negatively regulates cell growth in meningioma. PLoS One. \n                           9(9), e108228 (2014).","journal-title":"PLoS One."},{"issue":"20","key":"14845_CR22","doi-asserted-by":"publisher","first-page":"11057","DOI":"10.1073\/pnas.93.20.11057","volume":"93","author":"A Amendola","year":"1996","unstructured":"Amendola, A. et al. Induction of \u201ctissue\u201d transglutaminase in HIV pathogenesis: evidence for high rate of apoptosis of CD4+ T lymphocytes and accessory cells in lymphoid tissues. Proc. Natl. Acad. Sci USA \n                           93(20), 11057\u201362 (1996).","journal-title":"Proc. Natl. Acad. Sci USA"},{"issue":"2","key":"14845_CR23","doi-asserted-by":"publisher","first-page":"76","DOI":"10.2174\/1574889809666141111160124","volume":"9","author":"M Iannaccone","year":"2014","unstructured":"Iannaccone, M., Titta, F., Serretiello, E., Monfregola, M. & Gentile, V. Possible physiopathological effects of the transglutaminase activity on the molecular mechanisms responsible for human neurodegenerative diseases. Recent Pat. CNS Drug Discov. \n                           9(2), 76\u201384 (2014).","journal-title":"Recent Pat. CNS Drug Discov."},{"issue":"9","key":"14845_CR24","doi-asserted-by":"publisher","first-page":"e45209","DOI":"10.1371\/journal.pone.0045209","volume":"7","author":"I Caputo","year":"2012","unstructured":"Caputo, I. et al. Gliadin peptides induce tissue transglutaminase activation and ER-stress through Ca2+ mobilization in Caco-2 cells. PLoS One. \n                           7(9), e45209 (2012).","journal-title":"PLoS One."},{"issue":"10","key":"14845_CR25","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1002\/ar.22741","volume":"296","author":"YT Liu","year":"2013","unstructured":"Liu, Y. T. et al. Distribution of transglutaminase 6 in the central nervous system of adult mice. Anat. Rec. (Hoboken). \n                           296(10), 1576\u201387 (2013).","journal-title":"Anat. Rec. (Hoboken)."},{"issue":"9","key":"14845_CR26","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1002\/emmm.201000084","volume":"2","author":"SJ McConoughey","year":"2010","unstructured":"McConoughey, S. J. et al. Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington disease. EMBO Mol Med. \n                           2(9), 349\u201370 (2010).","journal-title":"EMBO Mol Med."},{"issue":"1","key":"14845_CR27","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1007\/s10875-012-9745-5","volume":"33","author":"T Rauhavirta","year":"2013","unstructured":"Rauhavirta, T. et al. Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study. J. Clin. Immunol. \n                           33(1), 134\u201342 (2013).","journal-title":"J. Clin. Immunol."},{"issue":"2","key":"14845_CR28","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.gene.2014.11.022","volume":"556","author":"A Kumar","year":"2015","unstructured":"Kumar, A. et al. Huntington\u2019s disease: an update of therapeutic strategies. Gene. \n                           556(2), 91\u20137 (2015).","journal-title":"Gene."},{"issue":"4","key":"14845_CR29","doi-asserted-by":"publisher","first-page":"e3","DOI":"10.1016\/j.neurobiolaging.2013.08.022","volume":"35","author":"MM Wilhelmus","year":"2014","unstructured":"Wilhelmus, M. M. & Drukarch, B. Tissue transglutaminase is a biochemical marker for Alzheimer\u2019s disease. Neurobiol. Aging. \n                           35(4), e3\u20134 (2014).","journal-title":"Neurobiol. Aging."},{"issue":"2","key":"14845_CR30","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.pharmthera.2014.05.010","volume":"144","author":"FI Tarazi","year":"2014","unstructured":"Tarazi, F. I., Sahli, Z. T., Wolny, M. & Mousa, S. A. Emerging therapies for Parkinson\u2019s disease: from bench to bedside. Pharmacol. Ther. \n                           144(2), 123\u201333 (2014).","journal-title":"Pharmacol. Ther."},{"issue":"6","key":"14845_CR31","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1038\/jcbfm.2013.53","volume":"33","author":"M Basso","year":"2013","unstructured":"Basso, M. & Ratan, R. R. Transglutaminase is a therapeutic target for oxidative stress, excitotoxicity and stroke: a new epigenetic kid on the CNS block. J. Cereb. Blood Flow Metab. \n                           33(6), 809\u201318 (2013).","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"14845_CR32","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.expneurol.2013.09.010","volume":"250","author":"M Muzzi","year":"2013","unstructured":"Muzzi, M., Coppi, E., Pugliese, A. M. & Chiarugi, A. Anticonvulsant effect of AMP by direct activation of adenosine A1 receptor. Exp. Neurol. \n                           250, 189\u201393 (2013).","journal-title":"Exp. Neurol."},{"issue":"4","key":"14845_CR33","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.neuropharm.2010.11.021","volume":"60","author":"E Landucci","year":"2011","unstructured":"Landucci, E., Scartabelli, T., Gerace, E., Moroni, F. & Pellegrini-Giampietro, D. E. CB1 receptors and post-ischemic brain damage: Studies on the toxic and neuroprotective effects of cannabinoids in rat organotypic hippocampal slices. Neuropharmacology. \n                           60(4), 674\u201382 (2011).","journal-title":"Neuropharmacology."},{"key":"14845_CR34","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/978-1-61779-536-7_29","volume":"846","author":"E Gerace","year":"2012","unstructured":"Gerace, E., Landucci, E., Scartabelli, T., Moroni, F. & Pellegrini-Giampietro, D. E. Rat hippocampal slice culture models for the evaluation of neuroprotective agents. Methods Mol. Biol. \n                           846, 343\u201354 (2012).","journal-title":"Methods Mol. Biol."},{"key":"14845_CR35","doi-asserted-by":"publisher","first-page":"3637","DOI":"10.1046\/j.1460-9568.1999.00786.x","volume":"11","author":"DE Pellegrini-Giampietro","year":"1999","unstructured":"Pellegrini-Giampietro, D. E. et al. 1-Aminoindan-1,5-dicarboxylic acid and (S)-(+)-2-(3\u2032-carboxybicyclo[1.1.1]pentyl)-glycine, two mGlu1 receptor-preferring antagonists, reduce neuronal death in in vitro and in vivo models of cerebral ischemia. Eur. J. Neurosci. \n                           11, 3637\u20133647 (1999a).","journal-title":"Eur. J. Neurosci."},{"key":"14845_CR36","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.nbd.2014.05.023","volume":"70","author":"E Gerace","year":"2014","unstructured":"Gerace, E. et al. PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca2+\u2009-permeable AMPA receptors. Neurobiol. Dis. \n                           70, 43\u201352 (2014).","journal-title":"Neurobiol. Dis."},{"key":"14845_CR37","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.neuropharm.2015.01.008","volume":"92","author":"E Gerace","year":"2015","unstructured":"Gerace, E. et al. Interplay between histone acetylation\/deacetylation and poly(ADP-ribosyl)ation in the development of ischemic tolerance in vitro. Neuropharmacology \n                           92, 125\u2013134 (2015).","journal-title":"Neuropharmacology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14845-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14845-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14845-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T08:26:25Z","timestamp":1671783985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14845-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,9]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["14845"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-14845-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,9]]},"assertion":[{"value":"19 July 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 November 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15146"}}