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Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures

Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(−) cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABA(A) receptors in the perinatal period. The most com...

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Autores principales: Cleary, Ryan T., Sun, Hongyu, Huynh, Thanhthao, Manning, Simon M., Li, Yijun, Rotenberg, Alexander, Talos, Delia M., Kahle, Kristopher T., Jackson, Michele, Rakhade, Sanjay N., Berry, Gerard, Jensen, Frances E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594228/
https://www.ncbi.nlm.nih.gov/pubmed/23536761
http://dx.doi.org/10.1371/journal.pone.0057148
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author Cleary, Ryan T.
Sun, Hongyu
Huynh, Thanhthao
Manning, Simon M.
Li, Yijun
Rotenberg, Alexander
Talos, Delia M.
Kahle, Kristopher T.
Jackson, Michele
Rakhade, Sanjay N.
Berry, Gerard
Jensen, Frances E.
author_facet Cleary, Ryan T.
Sun, Hongyu
Huynh, Thanhthao
Manning, Simon M.
Li, Yijun
Rotenberg, Alexander
Talos, Delia M.
Kahle, Kristopher T.
Jackson, Michele
Rakhade, Sanjay N.
Berry, Gerard
Jensen, Frances E.
author_sort Cleary, Ryan T.
collection PubMed
description Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(−) cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABA(A) receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in E(GABA.) Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures.
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spelling pubmed-35942282013-03-27 Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures Cleary, Ryan T. Sun, Hongyu Huynh, Thanhthao Manning, Simon M. Li, Yijun Rotenberg, Alexander Talos, Delia M. Kahle, Kristopher T. Jackson, Michele Rakhade, Sanjay N. Berry, Gerard Jensen, Frances E. PLoS One Research Article Neonatal seizures can be refractory to conventional anticonvulsants, and this may in part be due to a developmental increase in expression of the neuronal Na(+)-K(+)-2 Cl(−) cotransporter, NKCC1, and consequent paradoxical excitatory actions of GABA(A) receptors in the perinatal period. The most common cause of neonatal seizures is hypoxic encephalopathy, and here we show in an established model of neonatal hypoxia-induced seizures that the NKCC1 inhibitor, bumetanide, in combination with phenobarbital is significantly more effective than phenobarbital alone. A sensitive mass spectrometry assay revealed that bumetanide concentrations in serum and brain were dose-dependent, and the expression of NKCC1 protein transiently increased in cortex and hippocampus after hypoxic seizures. Importantly, the low doses of phenobarbital and bumetanide used in the study did not increase constitutive apoptosis, alone or in combination. Perforated patch clamp recordings from ex vivo hippocampal slices removed following seizures revealed that phenobarbital and bumetanide largely reversed seizure-induced changes in E(GABA.) Taken together, these data provide preclinical support for clinical trials of bumetanide in human neonates at risk for hypoxic encephalopathy and seizures. Public Library of Science 2013-03-11 /pmc/articles/PMC3594228/ /pubmed/23536761 http://dx.doi.org/10.1371/journal.pone.0057148 Text en © 2013 Cleary et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cleary, Ryan T.
Sun, Hongyu
Huynh, Thanhthao
Manning, Simon M.
Li, Yijun
Rotenberg, Alexander
Talos, Delia M.
Kahle, Kristopher T.
Jackson, Michele
Rakhade, Sanjay N.
Berry, Gerard
Jensen, Frances E.
Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures
title Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures
title_full Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures
title_fullStr Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures
title_full_unstemmed Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures
title_short Bumetanide Enhances Phenobarbital Efficacy in a Rat Model of Hypoxic Neonatal Seizures
title_sort bumetanide enhances phenobarbital efficacy in a rat model of hypoxic neonatal seizures
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594228/
https://www.ncbi.nlm.nih.gov/pubmed/23536761
http://dx.doi.org/10.1371/journal.pone.0057148
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