{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T18:53:09Z","timestamp":1776624789523,"version":"3.51.2"},"reference-count":30,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T00:00:00Z","timestamp":1370822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2013,7]]},"abstract":"Summary<\/jats:title>Purpose<\/jats:title>Kindling is a well\u2010established model of secondarily generalized partial seizures that is widely employed in the search for novel antiseizure drugs. During the kindling and postkindling acquisition phase, an active process of neuronal remodeling occurs. We tested the hypothesis that exposure to the voltage\u2010gated sodium channel blockers lamotrigine (LTG<\/jats:styled-content>) and carbamazepine (CBZ<\/jats:styled-content>) during the period of active remodeling will lead to a diminished therapeutic effect.<\/jats:p><\/jats:sec>Methods<\/jats:title>Two days after the last kindling stimulation, fully kindled rats were randomized to receive either 0.5% methyl cellulose (MC<\/jats:styled-content>), LTG<\/jats:styled-content> (30\u00a0mg\/kg), or CBZ<\/jats:styled-content> (40\u00a0mg\/kg). The effect of LTG<\/jats:styled-content> and CBZ<\/jats:styled-content> on behavioral seizure severity and electrographic afterdischarge duration (ADD<\/jats:styled-content>) was recorded. One week after this treatment, rats in both groups were rechallenged with LTG<\/jats:styled-content> 30 or CBZ<\/jats:styled-content> 40\u00a0mg\/kg and their seizure score and ADD<\/jats:styled-content> recorded. In vitro efficacy of LTG<\/jats:styled-content> on neuronal action potentials was also evaluated using whole cell current clamp recording in hippocampal brain slices obtained from kindled control rats, LTG\u2010sensitive kindled rats, and LTG\u2010resistant kindled rats.<\/jats:p><\/jats:sec>Key Findings<\/jats:title>When acutely administered 48\u00a0h after the last kindling stimulation, LTG<\/jats:styled-content> and CBZ<\/jats:styled-content> blocked the expression of behavioral seizures and reduced the ADD<\/jats:styled-content>. In contrast, a second challenge dose of LTG<\/jats:styled-content> or CBZ<\/jats:styled-content> administered after a 7\u2010day \u201cno drug, no stimulation\u201d period did not result in reduction of either the seizure score or the ADD<\/jats:styled-content>. Interestingly, the potassium channel opener, ezogabine, also known as retigabine (EZG<\/jats:styled-content>; 40\u00a0mg\/kg), blocked the expression of behavioral seizures at both time points evaluated (i.e., 2\u00a0days and 9\u00a0days after last stimulation). In vivo resistance to LTG<\/jats:styled-content> was associated with a similar reduction in the ability of LTG<\/jats:styled-content> to limit action potential firing in CA<\/jats:styled-content>1 neurons. LTG<\/jats:styled-content> (50\u00a0\u03bcm<\/jats:sc>) significantly decreased the number of action potentials generated by a depolarizing current pulse in neurons recorded from slices obtained from kindled control and LTG<\/jats:styled-content>\u2010sensitive rats, but not in slices obtained from LTG<\/jats:styled-content>\u2010resistant rats.<\/jats:p><\/jats:sec>Significance<\/jats:title>Collectively, results obtained from both in vivo and in vitro studies demonstrate that even a single exposure to the sodium channel blockers LTG<\/jats:styled-content>, or CBZ<\/jats:styled-content>, during the postkindling remodeling phase leads to an altered pharmacologic response to these two ASD<\/jats:styled-content>s, but not to EZG<\/jats:styled-content>. The LTG<\/jats:styled-content>\u2010 and CBZ<\/jats:styled-content>\u2010resistant amygdala kindled rats may serve as a useful model of therapy\u2010resistant epilepsy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12234","type":"journal-article","created":{"date-parts":[[2013,6,10]],"date-time":"2013-06-10T13:17:24Z","timestamp":1370870244000},"page":"1186-1194","source":"Crossref","is-referenced-by-count":41,"title":["Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: A novel experimental model of pharmacoresistant epilepsy"],"prefix":"10.1111","volume":"54","author":[{"given":"Ajay K.","family":"Srivastava","sequence":"first","affiliation":[{"name":"Anticonvulsant Drug Development Program University of Utah Salt Lake City Utah U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anitha B.","family":"Alex","sequence":"additional","affiliation":[{"name":"Anticonvulsant Drug Development Program University of Utah Salt Lake City Utah U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen S.","family":"Wilcox","sequence":"additional","affiliation":[{"name":"Anticonvulsant Drug Development Program University of Utah Salt Lake City Utah U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H. Steve","family":"White","sequence":"additional","affiliation":[{"name":"Anticonvulsant Drug Development Program University of Utah Salt Lake City Utah U.S.A"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,6,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(96)00162-3"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0953-816x.2001.01502.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1018549928277"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2008.01710.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-19-08312.1999"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0895-461"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00117-1"},{"key":"e_1_2_8_9_1","first-page":"441","article-title":"Molecular properties of brain sodium channels: an important target for anticonvulsant drugs","volume":"79","author":"Catterall WA","year":"1999","journal-title":"Adv Neurol"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(92)90065-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00168-4"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(98)00394-2"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.9.3260"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1999.7343"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3283117d67"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2007.00993.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2011.01.003"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(93)90058-F"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2004.03.009"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1575-05.2006"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209532200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1499-1654.2000.001514.x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(72)90177-0"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(97)00054-4"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh682"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10473"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2003.02710.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(95)00101-8"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2012.10.003"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb02034.x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00212-3"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fepi.12234","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.12234","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T02:04:50Z","timestamp":1696298690000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.12234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,10]]},"references-count":30,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["10.1111\/epi.12234"],"URL":"https:\/\/doi.org\/10.1111\/epi.12234","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,10]]}}}