{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T21:16:18Z","timestamp":1791148578661,"version":"4.1.0"},"reference-count":81,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2007,10,4]],"date-time":"2007-10-04T00:00:00Z","timestamp":1191456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2008,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      High levels of expression of the Na\n                      <jats:sup>+<\/jats:sup>\n                      \u2010K\n                      <jats:sup>+<\/jats:sup>\n                      \u20102Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      (NKCC1) cotransporter in immature neurons cause the accumulation of intracellular chloride and, therefore, a depolarized Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      equilibrium potential (E\n                      <jats:sub>Cl<\/jats:sub>\n                      ). This results in the outward flux of Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      through GABA\n                      <jats:sub>A<\/jats:sub>\n                      channels, the opposite direction compared with mature neurons, in which GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor activation is inhibitory because Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      flows into the cell. This outward flow of Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      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\n                      <jats:sup>\u2212<\/jats:sup>\n                      flux and causes a more negative GABA equilibrium potential (E\n                      <jats:sub>GABA<\/jats:sub>\n                      ) in immature neurons. We therefore tested whether bumetanide enhances the anticonvulsant action of phenobarbital in the neonatal brain\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Recurrent seizures were induced in the intact hippocampal preparation in vitro by continuous 5\u2010hour exposure to low\u2010Mg\n                      <jats:sup>2+<\/jats:sup>\n                      solution. The anticonvulsant efficacy of phenobarbital, bumetanide, and the combination of these drugs was studied\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <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>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Thus, alteration of Cl\n                      <jats:sup>\u2212<\/jats:sup>\n                      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\u2010life seizures. Ann Neurol 2007\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.21229","type":"journal-article","created":{"date-parts":[[2007,10,4]],"date-time":"2007-10-04T18:46:32Z","timestamp":1191523592000},"page":"222-235","source":"Crossref","is-referenced-by-count":236,"title":["Bumetanide enhances phenobarbital efficacy in a neonatal seizure model"],"prefix":"10.1002","volume":"63","author":[{"given":"Volodymyr I.","family":"Dzhala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey C.","family":"Brumback","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Staley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,2,27]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0301-0082(94)90049-3"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020973"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410010510"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0920-1211(94)90049-3"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(91)90243-S"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0168-0102(94)90025-6"},{"issue":"2","key":"e_1_2_6_8_2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1113\/jphysiol.1995.sp020882","article-title":"Synaptic GABAA activation induces Ca2+ rise in pyramidal cells and interneurons from rat neonatal hippocampal slices","volume":"487","author":"Leinekugel X","year":"1995","journal-title":"J Physiol"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90008-X"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00341-5"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn920"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2004.11.011"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(96)00964-8"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.09.026"},{"key":"e_1_2_6_15_2","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1523\/JNEUROSCI.04-03-00860.1984","article-title":"Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing response to gamma\u2010aminobutyric acid in rabbit hippocampus studied in vitro","volume":"4","author":"Mueller AL","year":"1984","journal-title":"J Neurosci"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021505"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1159\/000017380"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(99)00098-X"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-23-08822.2000"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-05-01840.2003"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0953-816X.2003.03152.x"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2003.19503.x"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20259"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410250302"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1754.2005.00638.x"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.64.4_Spec_No.459"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199908123410704"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0887-8994(02)00621-5"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000106944.59990.E6"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000157320.78071.6D"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1301"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.18.11295"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-001-0521-y"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.062471"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.107086"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(96)90197-6"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1159\/000244492"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80956-3"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1987.57.3.869"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1989.sp017762"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1071111"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.107086"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)00116-X"},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020649"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1133212"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.27.16237"},{"key":"e_1_2_6_47_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.1.211"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1999.00768.x"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2000.00156.x"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2002.02143.x"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.01.024"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1989.sp017814"},{"key":"e_1_2_6_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(92)90183-8"},{"key":"e_1_2_6_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(01)00122-X"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/290149a0"},{"key":"e_1_2_6_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1125"},{"key":"e_1_2_6_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410240502"},{"key":"e_1_2_6_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1988.59.1.259"},{"key":"e_1_2_6_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20972"},{"key":"e_1_2_6_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(03)00068-7"},{"key":"e_1_2_6_61_2","first-page":"309","article-title":"Cation\u2010chloride cotransporters in neuronal communication","volume":"15","author":"Delpire E","year":"2000","journal-title":"News Physiol Sci"},{"key":"e_1_2_6_62_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2004"},{"key":"e_1_2_6_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1095-6433(01)00420-2"},{"key":"e_1_2_6_64_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00172.2003"},{"key":"e_1_2_6_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(97)01147-8"},{"key":"e_1_2_6_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00485.x"},{"key":"e_1_2_6_67_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5233.99"},{"key":"e_1_2_6_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(98)00700-3"},{"key":"e_1_2_6_69_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.2000.83.1.406"},{"key":"e_1_2_6_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02121-1"},{"key":"e_1_2_6_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.1136"},{"key":"e_1_2_6_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2006.01.005"},{"key":"e_1_2_6_73_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00944.2004"},{"key":"e_1_2_6_74_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00138.2005"},{"key":"e_1_2_6_75_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222550499"},{"key":"e_1_2_6_76_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2003.tb07517.x"},{"key":"e_1_2_6_77_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199002083220604"},{"key":"e_1_2_6_78_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1995.03530190032031"},{"key":"e_1_2_6_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04404"},{"key":"e_1_2_6_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80642-X"},{"key":"e_1_2_6_81_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1076510"},{"key":"e_1_2_6_82_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602979103"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.21229","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.21229","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T21:57:28Z","timestamp":1696024648000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.21229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,2]]},"references-count":81,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2008,2]]}},"alternative-id":["10.1002\/ana.21229"],"URL":"https:\/\/doi.org\/10.1002\/ana.21229","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,2]]}}}