{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:47:24Z","timestamp":1787021244093,"version":"build-2736575974"},"reference-count":33,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,8,14]],"date-time":"2022-08-14T00:00:00Z","timestamp":1660435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Darigabat is an \u03b12\/3\/5 subunit\u2010selective positive allosteric modulator of GABA<jats:sub>A<\/jats:sub> receptors that has demonstrated broad\u2010spectrum activity in several preclinical models of epilepsy as well as in a clinical photoepilepsy trial. The objective here was to assess the acute antiseizure effect of darigabat in the mesial temporal lobe epilepsy (MTLE) mouse model of drug\u2010resistant focal seizures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The MTLE model is generated by single unilateral intrahippocampal injection of low dose (1 nmole) kainic acid in adult mice, and subsequent epileptiform activity is recorded following implantation of a bipolar electrode under general anesthesia. After a period of epileptogenesis (~4\u2009weeks), spontaneous and recurrent hippocampal paroxysmal discharges (HPD; focal seizures) are recorded using intracerebral electroencephalography. The number and cumulated duration of HPDs were recorded following administration of vehicle (PO), darigabat (0.3\u201310\u00a0mg\u2009kg<jats:sup>\u22121<\/jats:sup>, PO), and positive control diazepam (2\u00a0mg\u2009kg<jats:sup>\u22121<\/jats:sup>, IP).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Darigabat dose\u2010dependently reduced the expression of HPDs, demonstrating comparable efficacy profile to diazepam at doses of 3 and 10\u00a0mg\u2009kg<jats:sup>\u22121<\/jats:sup>.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Darigabat exhibited a robust efficacy profile in the MTLE model, a preclinical model of drug\u2010resistant focal epilepsy. A Phase II proof\u2010of\u2010concept placebo\u2010controlled, adjunctive\u2010therapy trial (NCT04244175) is ongoing to evaluate efficacy and safety of darigabat in patients with drug\u2010resistant focal seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13927","type":"journal-article","created":{"date-parts":[[2022,8,15]],"date-time":"2022-08-15T06:44:25Z","timestamp":1660545865000},"page":"1875-1882","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pronounced antiseizure activity of the subtype\u2010selective <scp>GABA<sub>A<\/sub><\/scp> positive allosteric modulator darigabat in a mouse model of drug\u2010resistant focal epilepsy"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4209-4821","authenticated-orcid":false,"given":"Rachel","family":"Gurrell","sequence":"first","affiliation":[{"name":"Cerevel Therapeutics  Cambridge Massachusetts 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