{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:19:23Z","timestamp":1790893163636,"version":"4.1.0"},"reference-count":939,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012632","name":"Nazarbayev University","doi-asserted-by":"crossref","award":["20122022CRP1616"],"award-info":[{"award-number":["20122022CRP1616"]}],"id":[{"id":"10.13039\/501100012632","id-type":"DOI","asserted-by":"crossref"}]},{"award":["20122022CRP1616"],"award-info":[{"award-number":["20122022CRP1616"]}],"id":[{"id":"https:\/\/ror.org\/052bx8q98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Epilepsy is a multifactorial disorder, yet routine management still focuses on neuronal excitation and insufficient inhibition, with antiseizure medications (ASMs) as the primary therapeutic strategy. This approach fails in roughly one-third of patients who develop drug-resistant epilepsy (DRE). Converging evidence links DRE with neuroinflammation, oxidative stress (OS), and mitochondrial dysfunction\u2014an interconnected distal pathophysiological triad that progressively lowers seizure thresholds yet remains peripheral to clinical epilepsy management. We map this triad mechanistically and show that ASMs modulate it beyond their anticonvulsant activity, while triad-targeting pharmacological, dietary, and botanical interventions independently reduce seizure susceptibility. Common precipitants are reinterpreted as acute activators of the distal triad, linking precipitant identification and patient agency to threshold elevation. Integrating these elements, we propose a threshold management framework for DRE, built on a revised reservoir model, and translate it into three structural priorities: mechanistic phenotyping to stratify patients by pathophysiological domain, dual-mechanism drug development, and trial designs suited to multicomponent, context-dependent interventions. Together, these proposals reframe epilepsy management from sequential pharmacological trials toward coordinated optimization of the full seizure threshold landscape.<\/jats:p>","DOI":"10.3390\/ijms27156606","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Anti-Inflammatory and Antioxidant Strategies in Epilepsy: From Molecular Mechanisms to Threshold Management"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6745-6035","authenticated-orcid":false,"given":"Alexander","family":"Trofimov","sequence":"first","affiliation":[{"name":"Laboratory of Neurophysiology, Department of Biology, School of Sciences and Humanities (SSH), Nazarbayev University, 53 Kabanbay Batyr Ave., Astana 010000, Kazakhstan"},{"name":"Laboratory of Neurobiology of Integrative Brain Functions, I.P. Pavlov Department of Physiology, Institute of Experimental Medicine, 12 Acad. Pavlov St., 197022 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5091-6795","authenticated-orcid":false,"given":"Ksenia","family":"Shcherbakova","sequence":"additional","affiliation":[{"name":"Independent Researcher, Montreal, QC H3Y 2W4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-1397","authenticated-orcid":false,"given":"Alexander","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Mechanisms of Neuronal Interactions, I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez Ave., 194223 St. Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6389-170X","authenticated-orcid":false,"given":"Burkitkan","family":"Akbay","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology, Department of Biology, School of Sciences and Humanities (SSH), Nazarbayev University, 53 Kabanbay Batyr Ave., Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9192-8636","authenticated-orcid":false,"given":"Orynbassar","family":"Karapina","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology, Department of Biology, School of Sciences and Humanities (SSH), Nazarbayev University, 53 Kabanbay Batyr Ave., Astana 010000, 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Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4805-1437","authenticated-orcid":false,"given":"Ayaulym","family":"Baktursyn","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology, Department of Biology, School of Sciences and Humanities (SSH), Nazarbayev University, 53 Kabanbay Batyr Ave., Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5879-3443","authenticated-orcid":false,"given":"Madina","family":"Isseyeva","sequence":"additional","affiliation":[{"name":"Laboratory of Neurophysiology, Department of Biology, School of Sciences and Humanities (SSH), Nazarbayev University, 53 Kabanbay Batyr Ave., Astana 010000, 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(SSH), Nazarbayev University, 53 Kabanbay Batyr Ave., Astana 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, March 11). 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