{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1363670321322798720.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1002/ana.21229"}},{"identifier":{"@type":"URI","@value":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fana.21229"}},{"identifier":{"@type":"URI","@value":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ana.21229"}}],"dc:title":[{"@value":"Bumetanide enhances phenobarbital efficacy in a neonatal seizure model"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>High levels of expression of the Na<jats:sup>+</jats:sup>‐K<jats:sup>+</jats:sup>‐2Cl<jats:sup>−</jats:sup> (NKCC1) cotransporter in immature neurons cause the accumulation of intracellular chloride and, therefore, a depolarized Cl<jats:sup>−</jats:sup> equilibrium potential (E<jats:sub>Cl</jats:sub>). This results in the outward flux of Cl<jats:sup>−</jats:sup> through GABA<jats:sub>A</jats:sub> channels, the opposite direction compared with mature neurons, in which GABA<jats:sub>A</jats:sub> receptor activation is inhibitory because Cl<jats:sup>−</jats:sup> flows into the cell. This outward flow of Cl<jats:sup>−</jats:sup> in neonatal neurons is excitatory and contributes to a greater seizure propensity and poor electroencephalographic response to GABAergic anticonvulsants such as phenobarbital and benzodiazepines. Blocking the NKCC1 transporter with bumetanide prevents outward Cl<jats:sup>−</jats:sup> flux and causes a more negative GABA equilibrium potential (E<jats:sub>GABA</jats:sub>) in immature neurons. We therefore tested whether bumetanide enhances the anticonvulsant action of phenobarbital in the neonatal brain</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Recurrent seizures were induced in the intact hippocampal preparation in vitro by continuous 5‐hour exposure to low‐Mg<jats:sup>2+</jats:sup> solution. The anticonvulsant efficacy of phenobarbital, bumetanide, and the combination of these drugs was studied</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Phenobarbital failed to abolish or depress recurrent seizures in 70% of hippocampi. In contrast, phenobarbital in combination with bumetanide abolished seizures in 70% of hippocampi and significantly reduced the frequency, duration, and power of seizures in the remaining 30%</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Thus, alteration of Cl<jats:sup>−</jats:sup> transport by bumetanide enables the anticonvulsant action of phenobarbital in immature brain. This is a mechanistic demonstration of rational anticonvulsant polypharmacy. The combination of these agents may comprise an effective therapy for early‐life seizures. Ann Neurol 2007</jats:p></jats:sec>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1383670321322798720","@type":"Researcher","foaf:name":[{"@value":"Volodymyr I. Dzhala"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670321322798721","@type":"Researcher","foaf:name":[{"@value":"Audrey C. Brumback"}]},{"@id":"https://cir.nii.ac.jp/crid/1383670321322798722","@type":"Researcher","foaf:name":[{"@value":"Kevin J. Staley"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"03645134"},{"@type":"EISSN","@value":"15318249"}],"prism:publicationName":[{"@value":"Annals of Neurology"}],"dc:publisher":[{"@value":"Wiley"}],"prism:publicationDate":"2008-02","prism:volume":"63","prism:number":"2","prism:startingPage":"222","prism:endingPage":"235"},"reviewed":"false","dc:rights":["http://onlinelibrary.wiley.com/termsAndConditions#vor"],"url":[{"@id":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fana.21229"},{"@id":"https://onlinelibrary.wiley.com/doi/pdf/10.1002/ana.21229"}],"createdAt":"2007-10-04","modifiedAt":"2023-09-30","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360285707507468032","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Chloride Dysregulation, Seizures, and Cerebral Edema: A Relationship with Therapeutic Potential"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567187849128192","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"The Pharmacological Assessment of GABA<sub>A</sub>Receptor Activation in Experimental Febrile Seizures in Mice"}]},{"@id":"https://cir.nii.ac.jp/crid/1360568467112154752","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Chloride homeodynamics underlying modal shifts in cellular and network oscillations"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1002/ana.21229"},{"@type":"CROSSREF","@value":"10.1523/eneuro.0429-18.2019_references_DOI_YGR7mdih3N7wgoZVkFO060sIxHx"},{"@type":"CROSSREF","@value":"10.1016/j.tins.2017.03.006_references_DOI_YGR7mdih3N7wgoZVkFO060sIxHx"},{"@type":"CROSSREF","@value":"10.1016/j.neures.2020.02.010_references_DOI_YGR7mdih3N7wgoZVkFO060sIxHx"}]}