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

被引：116

作者：

Cleary, Ryan T. ^{[1
]}

Sun, Hongyu ^{[1
]}

Thanhthao Huynh ^{[1
]}

Manning, Simon M. ^{[1
,3
]}

Li, Yijun ^{[2
]}

Rotenberg, Alexander ^{[1
]}

Talos, Delia M. ^{[1
]}

Kahle, Kristopher T. ^{[5
,6
]}

Jackson, Michele ^{[1
]}

Rakhade, Sanjay N. ^{[1
]}

Berry, Gerard ^{[2
]}

Jensen, Frances E. ^{[1
,4
]}

机构：

[1] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[2] Childrens Hosp, Div Genet & Metab, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Div Newborn Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Program Neurobiol, Boston, MA USA

[5] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[6] Harvard Univ, Sch Med, Boston, MA USA

来源：

PLOS ONE | 2013年 / 8卷 / 03期

基金：

美国国家卫生研究院;

关键词：

NA-K-2CL COTRANSPORTER NKCC1; CRITICALLY ILL INFANTS; DEVELOPING BRAIN; ANTIEPILEPTIC DRUGS; APOPTOTIC NEURODEGENERATION; STATUS EPILEPTICUS; IMMATURE BRAIN; HIPPOCAMPUS; GABA; PHARMACOKINETICS;

D O I：

10.1371/journal.pone.0057148

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 56 条

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