{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T16:46:00Z","timestamp":1789058760934,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research (RFBR)","doi-asserted-by":"publisher","award":["20-015-00127"],"award-info":[{"award-number":["20-015-00127"]}],"id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroglial apoptosis and neuroinflammation play an important role in epileptogenesis. The aim of this study is to evaluate neuronal and glial apoptosis in association with neuroinflammation in brain epileptic focus and inflammatory changes in blood in patients with focal drug-resistant epilepsy (DRE). Pathological changes in the temporal lobe in epilepsy (histology, transmission electron microscopy), levels of apoptotic and neuroinflammatory proteins: active caspase-3 (immunohistochemistry), full-length form caspase-3, caspase-9, FAS, FAS-L, NF-kB, TNF-\u03b1, p53 (Western blot), and cytokine levels in blood: IL-1\u03b2, IL-2, IL-4, IL-7, TNF-\u03b1, etc. (multiplex analysis) were studied. In the present work, ultrastructural and immunohistochemical apoptotic signs were found in neurons and oligodendrocytes in the temporal lobe of DRE patients. Levels of proinflammatory cytokines that play a role in apoptosis (TNF-\u03b1, FAS, NF-kB) were increased. The blood concentration of IL-4, IL-7, TNF-\u03b1 is increased and IL-2 is reduced. Oligodendroglial apoptosis has been shown to play an important role in DRE pathogenesis and to explain demyelination. Thus, a comprehensive analysis of revealed changes in the blood and brain in DRE patients showed the neuroinflammation in the epileptic focus, which was combined with the development of apoptosis of glial cells and neurons. This creates conditions for the development of drug resistance and the epilepsy progression.<\/jats:p>","DOI":"10.3390\/ijms232012561","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T22:19:53Z","timestamp":1666217993000},"page":"12561","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Relationship between Neuroglial Apoptosis and Neuroinflammation in the Epileptic Focus of the Brain and in the Blood of Patients with Drug-Resistant Epilepsy"],"prefix":"10.3390","volume":"23","author":[{"given":"Tatiana V.","family":"Sokolova","sequence":"first","affiliation":[{"name":"Polenov Neurosurgical Institute\u2014Branch of the Almazov National Medical Centre, 197341 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia M.","family":"Zabrodskaya","sequence":"additional","affiliation":[{"name":"Polenov Neurosurgical Institute\u2014Branch of the Almazov National Medical Centre, 197341 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7810-0832","authenticated-orcid":false,"given":"Anastasia V.","family":"Litovchenko","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia M.","family":"Paramonova","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vugar R.","family":"Kasumov","sequence":"additional","affiliation":[{"name":"Department of Neurology, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana V.","family":"Kravtsova","sequence":"additional","affiliation":[{"name":"Polenov Neurosurgical Institute\u2014Branch of the Almazov National Medical Centre, 197341 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina N.","family":"Skiteva","sequence":"additional","affiliation":[{"name":"Polenov Neurosurgical Institute\u2014Branch of the Almazov National Medical Centre, 197341 St. Petersburg, Russia"},{"name":"State Scientific Center of the Russian Federation, Institute of Biomedical Problems of the Russian Academy of Sciences, 123007 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9721-3827","authenticated-orcid":false,"given":"Daria A.","family":"Sitovskaya","sequence":"additional","affiliation":[{"name":"Polenov Neurosurgical Institute\u2014Branch of the Almazov National Medical Centre, 197341 St. Petersburg, Russia"},{"name":"Department of Neurology, St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9763-504X","authenticated-orcid":false,"given":"Elena D.","family":"Bazhanova","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia"},{"name":"Golikov Research Center of Toxicology, 192019 St. Petersburg, Russia"},{"name":"Laboratory of Apoptosis Investigation, Astrakhan State University, 414040 Astrakhan, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106750","DOI":"10.1016\/j.yebeh.2019.08.025","article-title":"Structural findings in patients with pharmacoresistant temporal epilepsy after anterior temporal lobectomy with a history of status epilepticus","volume":"101","author":"Bersnev","year":"2019","journal-title":"Epilepsy Behav."},{"key":"ref_2","first-page":"1","article-title":"An insight into the current understanding of status epilepticus: From concept to management","volume":"5","year":"2021","journal-title":"J. Neurol. Res. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"107993","DOI":"10.1016\/j.yebeh.2021.107993","article-title":"Use of extended-release and immediate-release anti-seizure medications with a long half-life to improve adherence in epilepsy: A guide for clinicians","volume":"120","author":"Gidal","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107967","DOI":"10.1016\/j.yebeh.2021.107967","article-title":"Valproic acid-induced encephalopathy: A review of clinical features, risk factors, diagnosis, and treatment","volume":"120","author":"Wu","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1111\/epi.13121","article-title":"A definition and classification of status epilepticus\u2014Report of the ILAE Task Force on Classification of Status Epilepticus","volume":"56","author":"Trinka","year":"2015","journal-title":"Epilepsia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1093\/neuros\/nyx138","article-title":"Treatment of Mesiotemporal Lobe Epilepsy: Which Approach is Favorable?","volume":"81","author":"Schmeiser","year":"2017","journal-title":"Neurosurgery"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.neuropharm.2011.07.038","article-title":"Progress on the issue of excitotoxic injury modifi cation vs. real neuroprotection; implications for post-traumatic epilepsy","volume":"61","author":"Sloviter","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1586\/erd.11.64","article-title":"Transcranial near-infrared laser therapy applied to promote clinical recovery in acute and chronic neurodegenerative diseases","volume":"9","author":"Lapchak","year":"2012","journal-title":"Expert Rev. Med. Devices"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s10517-020-04747-3","article-title":"Functional Imbalance of Glutamate- and GABAergic Neuronal Systems in the Pathogenesis of Focal Drug-Resistant Epilepsy in Humans","volume":"168","author":"Sazhina","year":"2020","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_10","first-page":"22","article-title":"Apoptosis of brain cells in epileptic focus at drug-resistant temporal lobe epilepsy","volume":"4","author":"Sokolova","year":"2017","journal-title":"Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3389\/fncel.2013.00110","article-title":"Contribution of apoptosis-associated signaling pathways to epileptogenesis: Lessons from Bcl-2 family knockouts","volume":"7","author":"Henshall","year":"2013","journal-title":"Front. Cell. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.17116\/patol2020820615","article-title":"Structural heterogeneity of epileptic foci in local drug-resistant epilepsy","volume":"82","author":"Sitovskaya","year":"2020","journal-title":"Arkhiv Patol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"a022434","DOI":"10.1101\/cshperspect.a022434","article-title":"Role of Astrocytes in Epilepsy","volume":"5","author":"Coulter","year":"2015","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1046\/j.1460-9568.2003.02874.x","article-title":"Expression and activation of caspase 3 following status epilepticus in the rat","volume":"18","author":"Narkilahti","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1080\/21691401.2019.1671428","article-title":"Fyn gene silencing reduces oligodendrocytes apoptosis through inhibiting ERK1\/2 phosphorylation in epilepsy","volume":"48","author":"Luo","year":"2020","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1038\/sj.jcbfm.9600149","article-title":"Epilepsy and apoptosis pathways","volume":"25","author":"Henshall","year":"2005","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"819\u201425","DOI":"10.1101\/gad.1077403","article-title":"Caspases signal not only apoptosis but also antigen-induced activation in cells of the immune system","volume":"17","author":"Newton","year":"2003","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e99300","DOI":"10.15252\/embj.201899300","article-title":"Regulation of death receptor signaling by the autophagy protein TP53INP2","volume":"38","author":"Ivanova","year":"2019","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1006\/jsbi.2000.4254","article-title":"Review: Nuclear events in apoptosis","volume":"129","author":"Robertson","year":"2000","journal-title":"J. Struct. Biol."},{"key":"ref_20","first-page":"385","article-title":"Apoptosis. Signaling pathways and changes in the water and ionic balance of the cell","volume":"49","author":"Shirokova","year":"2007","journal-title":"Cytology"},{"key":"ref_21","first-page":"411","article-title":"Markers of neuroinflammation and apoptosis in the temporal lobe of patients with drug-resistent epilepsy","volume":"57","author":"Litovchenko","year":"2021","journal-title":"J. Evol. Biochem. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1093\/brain\/awv067","article-title":"Astrocyte uncoupling as a cause of human temporal lobe epilepsy","volume":"136","author":"Bedner","year":"2015","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1007\/s11055-005-0103-4","article-title":"Induction of NO synthase and glial acidic fibrillary protein in astrocytes in the temporal cortex of the rat with audiogenic epileptiform reactions","volume":"35","author":"Kalinichenko","year":"2005","journal-title":"Neurosci. Behav. Physiol."},{"key":"ref_24","first-page":"97","article-title":"Apoptosis, Bcl-2 family proteins and caspases: The ABCs of seizure-damage and epileptogenesis","volume":"1","author":"Engel","year":"2009","journal-title":"Int. J. Physiol. Pathophysiol. Pharmacol."},{"key":"ref_25","first-page":"4516","article-title":"The relationship between the occurrence of intractable epilepsy with glial cells and myelin sheath\u2014an experimental study","volume":"20","author":"Hu","year":"2016","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.neuroscience.2017.01.035","article-title":"Chronic demyelination-induced seizures","volume":"27","author":"Lapato","year":"2017","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.brainres.2015.09.027","article-title":"Alterations in hippocampal myelin and oligodendrocyte precursor cells during epileptogenesis","volume":"19","author":"Luo","year":"2015","journal-title":"Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.expneurol.2016.03.009","article-title":"The multifaceted role of astrocytes in regulating myelination","volume":"283","author":"Lindsay","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.bbadis.2006.12.003","article-title":"Cell cycle molecules define a pathway required for neuron death in development and disease","volume":"1772","author":"Greene","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1046\/j.1471-4159.2000.741215.x","article-title":"Involvement of caspase-3-like protease in the mechanism of cell death following fokally evoked limbic seizures","volume":"74","author":"Henshall","year":"2000","journal-title":"Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fimmu.2019.00085","article-title":"Cell Type-Specific Roles of NF-\u03baB Linking Inflammation and Thrombosis","volume":"10","author":"Mussbacher","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/cdd.2011.155","article-title":"Regulation of CD95\/Fas signaling at the DISC","volume":"19","author":"Lavrik","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"631821","DOI":"10.3389\/fimmu.2021.631821","article-title":"Neutrophils: Many ways to die","volume":"12","author":"Ortega","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1042\/BCJ20210139","article-title":"Inhibitory feedback control of NF-\u03baB signalling in health and disease","volume":"478","author":"Prescott","year":"2021","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1016\/j.celrep.2018.10.002","article-title":"Differential Roles of IL-2 Signaling in Developing versus Mature Tregs","volume":"25","author":"Fan","year":"2018","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.neulet.2009.07.013","article-title":"Interleukin-2 deficiency-induced T cell autoimmunity in the mouse brain","volume":"463","author":"Huang","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Wojtulewicz, K., Krawczy\u0144ska, A., Tomaszewska-Zaremba, D., W\u00f3jcik, M., and Herman, A.P. (2020). Effect of Acute and Prolonged Inflammation on the Gene Expression of Proinflammatory Cytokines and Their Receptors in the Anterior Pituitary Gland of Ewes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186939"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12561\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:35Z","timestamp":1760144255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":37,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012561"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012561","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,19]]}}}