{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:19:11Z","timestamp":1790191151265,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T00:00:00Z","timestamp":1620259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["274\/15\u20101"],"award-info":[{"award-number":["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":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Bumetanide was suggested as an adjunct to phenobarbital for suppression of neonatal seizures. This suggestion was based on the idea that bumetanide, by reducing intraneuronal chloride accumulation through inhibition of the Na\u2010K\u20102Cl cotransporter NKCC1, may attenuate or abolish depolarizing \u03b3\u2010aminobutyric acid (GABA) responses caused by birth asphyxia. However, a first proof\u2010of\u2010concept clinical trial failed. This could have had several reasons, including bumetanide's poor brain penetration, the wide cellular NKCC1 expression pattern in the brain, and problems with the general concept of NKCC1\u2019s role in neonatal seizures. We recently replicated the clinical failure of bumetanide to potentiate phenobarbital's effect in a novel rat model of birth asphyxia. In this study, a clinically relevant dose (0.3\u00a0mg\/kg) of bumetanide was used that does not lead to NKCC1\u2010inhibitory brain levels. The aim of the present experiments was to examine whether a much higher dose (10\u00a0mg\/kg) of bumetanide is capable of potentiating phenobarbital in this rat model. Furthermore, the effects of the two lipophilic bumetanide derivatives, the ester prodrug <jats:italic>N,N<\/jats:italic>\u2010dimethylaminoethylester of bumetanide (DIMAEB) and the benzylamine derivative bumepamine, were examined at equimolar doses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intermittent asphyxia was induced for 30\u00a0min by exposing male and female P11 rat pups to three 7\u00a0+\u00a03\u00a0min cycles of 9% and 5% O<jats:sub>2<\/jats:sub> at constant 20% CO<jats:sub>2<\/jats:sub>. All control pups exhibited neonatal seizures after the asphyxia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Even at 10\u00a0mg\/kg, bumetanide did not potentiate the effect of a submaximal dose (15\u00a0mg\/kg) of phenobarbital on seizure incidence, whereas a significant suppression of neonatal seizures was determined for combinations of phenobarbital with DIMAEB or, more effectively, bumepamine, which, however, does not inhibit NKCC1. Of interest, the bumepamine\/phenobarbital combination prevented the neurodegenerative consequences of asphyxia and seizures in the hippocampus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Both bumepamine and DIMAEB are promising tools that may help to develop more effective lead compounds for clinical trials.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16912","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T04:13:19Z","timestamp":1620360799000},"page":"1460-1471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A combination of phenobarbital and the bumetanide derivative bumepamine prevents neonatal seizures and subsequent hippocampal neurodegeneration in a rat model of birth asphyxia"],"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 Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"K\u00e4ufer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover 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 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 Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birthe","family":"Gericke","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology, and Pharmacy University of Veterinary Medicine Hannover Hannover Germany"},{"name":"Center for Systems Neuroscience Hannover Hannover Germany"}],"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, 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