{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:38:34Z","timestamp":1760143114232,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T00:00:00Z","timestamp":1706054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Maryland Innovation Initiative (MII) Phase 1","award":["US10525024B2","RO1HD090884","IDDRC P50HD103538"],"award-info":[{"award-number":["US10525024B2","RO1HD090884","IDDRC P50HD103538"]}]},{"name":"Development of TrkB antagonist ANA12 as novel adjunct treatment for refractory seizures in neonates; Johns Hopkins University","award":["US10525024B2","RO1HD090884","IDDRC P50HD103538"],"award-info":[{"award-number":["US10525024B2","RO1HD090884","IDDRC P50HD103538"]}]},{"name":"National Institute of Health","award":["US10525024B2","RO1HD090884","IDDRC P50HD103538"],"award-info":[{"award-number":["US10525024B2","RO1HD090884","IDDRC P50HD103538"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg\/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg\/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg\/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10\u201320 mg\/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.<\/jats:p>","DOI":"10.3390\/ijms25031447","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T03:59:42Z","timestamp":1706155182000},"page":"1447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures"],"prefix":"10.3390","volume":"25","author":[{"given":"Preeti","family":"Vyas","sequence":"first","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ira","family":"Chaturvedi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-1370","authenticated-orcid":false,"given":"Joseph","family":"Scafidi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5136-9594","authenticated-orcid":false,"given":"Shilpa D.","family":"Kadam","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA"},{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl E.","family":"Stafstrom","sequence":"additional","affiliation":[{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1111\/epi.14671","article-title":"Response to antiseizure medications in neonates with acute symptomatic seizures","volume":"60","author":"Glass","year":"2019","journal-title":"Epilepsia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1212\/01.WNL.0000157320.78071.6D","article-title":"Neonatal seizures: After all these years we still love what doesn\u2019t work","volume":"64","author":"Sankar","year":"2005","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11987","DOI":"10.1038\/s41598-018-30486-7","article-title":"Dose-dependent reversal of KCC2 hypofunction and phenobarbital-resistant neonatal seizures by ANA12","volume":"8","author":"Carter","year":"2018","journal-title":"Sci. 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