{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T01:09:46Z","timestamp":1785287386402,"version":"3.55.0"},"reference-count":48,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T00:00:00Z","timestamp":1691712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003769","name":"Eisai","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild\u2010to\u2010moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of \u03b3\u2010aminobutyric acid transporter\u20101, and to test its seizure suppression effects in a rat model of chronic MTLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100\u2009mg\/kg\/day of E2730 subcutaneously for 1\u2009week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid\u2010induced status epilepticus, and 9\u2009weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video\u2010electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Plasma levels following continuous infusion of E2730 showed a clear dose\u2010related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48\u2009h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose\u2010dependent manner, with 65% of rats becoming seizure\u2010free at the highest dose tested. Mean seizure class did not differ between the treatment groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>This study shows that continuous subcutaneous infusion of E2730 over 7\u2009days results in a marked, dose\u2010dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.17735","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:30:34Z","timestamp":1691141434000},"page":"2806-2817","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["E2730, an uncompetitive \u03b3\u2010aminobutyric acid transporter\u20101 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-4654","authenticated-orcid":false,"given":"Idrish","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Neuroscience Monash University  Melbourne Victoria Australia"},{"name":"University of Melbourne  Parkville Victoria 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