{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T09:40:01Z","timestamp":1749807601160,"version":"3.41.0"},"reference-count":43,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["RSP2025R131"],"award-info":[{"award-number":["RSP2025R131"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Status epilepticus (SE) is a condition of neurological emergency, which precipitates various functional and morphological changes in the brain. Due to the risk of drug resistance associated with SE, this study aimed to evaluate a multitargeted approach to treat SE by combining clinically used antiseizure drugs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we intraperitoneally administered tiagabine (TGB), levetiracetam (LEV), and perampanel (PER) alone and in combination as a duo and trio therapy after 30\u2009min of SE in electrode\u2010implanted male Sprague\u2013Dawley rats subjected to lithium\u2013pilocarpine\u2010induced convulsive SE. The rats were monitored for SE\u2010associated behavioral and electroencephalographic (EEG) changes. Moreover, at the end of the experiment, rats were sacrificed and brains were excised for biochemical and histopathological evaluation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The control rats showed behavioral progression to the seizure of Stages 4\u20135 with 30\u201340\u2009min of pilocarpine administration along with the appearance of uninterrupted fully blown epileptic spikes on EEG noted up to 2\u2009h. The rats treated with TGB, LEV, and PER alone failed to provide behavioral and ictal attenuation. However, when combinations were tested, there was an improvement in seizure presentation while TGB\u2009+\u2009PER and LEV\u2009+\u2009PER also reversed SE\u2010associated electrographic changes. However, the most prominent seizure attenuation was noted in rats receiving trio therapy with TGB, LEV, and PER. Moreover, the trio\u2010treated rats demonstrated marked protection from SE\u2010induced oxidative stress and morphological alterations in different regions of the brains.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>We observed that intraperitoneal administration of TGB, LEV, and PER alone did not significantly alter the ictal activity recorded by EEG but pharmacological manipulation of acutely coadministered drugs caused a reduction of electrographic, biochemical, and histopathological eruptions providing preclinical evidence of a novel multitargeted combination treatment to ameliorate the acute SE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Plain Language Summary<\/jats:title><jats:p>This study investigates and compares the efficacy of mono\u2010 and polytherapy approach to counter the behavioral, electrographic, and histopathlogical manifestations of status epilepticus. The tiagabine as monotherapy was administered after 30\u2009min of uninterrupted SE, and the outcomes were compared with levetiracetam and perampanel alone as well as their duo and trio combinations. We noted that combining the low doses of tiagabine, levetiracetam, and perampanel notably interrupted the seizure progression through distinct mechanism in rat model of status epilepticus. Thus, we conclude that this novel combination may be a promising multitargeted approach for management of status epilepticus.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.13141","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T17:34:29Z","timestamp":1744133669000},"page":"669-681","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Polypharmacy with tiagabine, levetiracetam, and perampanel in status epilepticus: Insights from EEG, biochemical, and histopathological studies in rats"],"prefix":"10.1002","volume":"10","author":[{"given":"Sana","family":"Javaid","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Bahauddin Zakariya University  Multan Pakistan"},{"name":"Department of Pharmacy The Women University  Multan Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faleh","family":"Alqahtani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology College of Pharmacy, King Saud University  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abida","family":"Parveen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Bahauddin Zakariya University  Multan Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Waseem","family":"Ashraf","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Bahauddin Zakariya University  Multan Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zohabia","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Bahauddin Zakariya University  Multan Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Syed Muhammad Muneeb","family":"Anjum","sequence":"additional","affiliation":[{"name":"The Institute of Pharmaceutical Sciences University of Veterinary and Animal Sciences  Lahore Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanveer","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Institut Pour l'Avanc\u00e9e des Biosciences, Centre de Recherche UGA\/INSERM U1209\/CNRS 5309 Universit\u00e9 Grenoble Alpes  Grenoble France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1337-8574","authenticated-orcid":false,"given":"Imran","family":"Imran","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Bahauddin Zakariya University  Multan Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/children9101586"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/0972-2327.56312"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2015.1045881"},{"issue":"9","key":"e_1_2_13_5_1","article-title":"Anticonvulsant therapy for status epilepticus","volume":"4","author":"Prasad K","year":"2005","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.01180.2007"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz283"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.14581\/jer.21023"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.08.004"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2012.08.022"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph13110340"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(83)90136-5"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2008.04.019"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(95)00835-7"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(94)90067-1"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.2000.tb00112.x"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsps.2022.03.003"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2011.03109.x"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsps.2023.101930"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.339"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13360"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.12787"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2018.09.016"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(72)90177-0"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115935"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.4c00962"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu15030666"},{"issue":"5","key":"e_1_2_13_28_1","first-page":"489","article-title":"Anxiolytic potential of resveratrol and rufinamide combination by modulating GABA\u2010ergic transmission: insights from experiments, molecular docking and dynamics simulations","volume":"74","author":"Parveen A","year":"2023","journal-title":"J Physiol Pharmacol"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(19)52451\u20106"},{"volume-title":"Paxinos and Franklin's the mouse brain in stereotaxic coordinates","year":"2001","author":"Paxinos G","key":"e_1_2_13_30_1"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2014.11.008"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1535-7597.2003.03104.x"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.62402.x"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.05.021"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308208101"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)01884-5"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2009.12.007"},{"key":"e_1_2_13_38_1","first-page":"947","article-title":"AMPA receptors in epilepsy and as targets for antiepileptic drugs\u2014PubMed","volume":"79","author":"Rogawski MA","year":"1999","journal-title":"Adv Neurol"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2016.09.028"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2017.06.002"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2010.01.010"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2004.04537.x"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2021.688086"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.4103\/1735-5362.327505"}],"container-title":["Epilepsia Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi4.13141","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T09:08:17Z","timestamp":1749805697000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi4.13141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,8]]},"references-count":43,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/epi4.13141"],"URL":"https:\/\/doi.org\/10.1002\/epi4.13141","archive":["Portico"],"relation":{},"ISSN":["2470-9239","2470-9239"],"issn-type":[{"type":"print","value":"2470-9239"},{"type":"electronic","value":"2470-9239"}],"subject":[],"published":{"date-parts":[[2025,4,8]]},"assertion":[{"value":"2024-07-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}