{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:19:10Z","timestamp":1790191150903,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Lo 274\/15\u20101"],"award-info":[{"award-number":["Lo 274\/15\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Neonatal seizures are the most frequent type of neurological emergency in newborn infants, often being a consequence of prolonged perinatal asphyxia. Phenobarbital is currently the most widely used antiseizure drug for treatment of neonatal seizures, but fails to stop them in ~50% of cases. In a neonatal hypoxia\u2010only model based on 11\u2010day\u2010old (P11) rats, the NKCC1 inhibitor bumetanide was reported to potentiate the antiseizure activity of phenobarbital, whereas it was ineffective in a human trial in neonates. The aim of this study was to evaluate the effect of clinically relevant doses of bumetanide as add\u2010on to phenobarbital on neonatal seizures in a noninvasive model of birth asphyxia in P11 rats, designed for better translation to the human term neonate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intermittent asphyxia was induced for 30\u00a0minutes by exposing the rat pups to three 7\u00a0+\u00a03\u2013minute cycles of 9% and 5% O<jats:sub>2<\/jats:sub> at constant 20% CO<jats:sub>2<\/jats:sub>. Drug treatments were administered intraperitoneally either before or immediately after asphyxia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All untreated rat pups had seizures within 10\u00a0minutes after termination of asphyxia. Phenobarbital significantly blocked seizures when applied before asphyxia at 30\u00a0mg\/kg but not 15\u00a0mg\/kg. Administration of phenobarbital after asphyxia was ineffective, whereas midazolam (0.3 or 1\u00a0mg\/kg) exerted significant antiseizure effects when administered before or after asphyxia. In general, focal seizures were more resistant to treatment than generalized convulsive seizures. Bumetanide (0.3\u00a0mg\/kg) alone or in combination with phenobarbital (15 or 30\u00a0mg\/kg) exerted no significant effect on seizure occurrence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>The data demonstrate that bumetanide does not increase the efficacy of phenobarbital in a model of birth asphyxia, which is consistent with the negative data of the recent human trial. The translational data obtained with the novel rat model of birth asphyxia indicate that it is a useful tool to evaluate novel treatments for neonatal seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16778","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T11:26:13Z","timestamp":1606821973000},"page":"920-934","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0490-2648","authenticated-orcid":false,"given":"Marie","family":"Johne","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"R\u00f6mermann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5391-555X","authenticated-orcid":false,"given":"Philip","family":"Hampel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1980-7133","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Gailus","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Theilmann","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2452-9032","authenticated-orcid":false,"given":"Tommi","family":"Ala\u2010Kurikka","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Biosciences and Neuroscience Center (HiLIFE) University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Kaila","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Biosciences and Neuroscience Center (HiLIFE) University of Helsinki Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9648-8973","authenticated-orcid":false,"given":"Wolfgang","family":"L\u00f6scher","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12]]},"reference":[{"key":"e_1_2_9_2_1","article-title":"The ILAE classification of seizures & the epilepsies: modification for seizures in the neonate. 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