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Bumetanide enhances phenobarbital efficacy in a neonatal seizure model

Objectives High levels of expression of the Na+‐K+‐2Cl− (NKCC1) cotransporter in immature neurons cause the accumulation of intracellular chloride and, therefore, a depolarized Cl− equilibrium potential (ECl). This results in the outward flux of Cl− through GABAA channels, the opposite direction com...

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Published in:Annals of neurology 2008-02, Vol.63 (2), p.222-235
Main Authors: Dzhala, Volodymyr I., Brumback, Audrey C., Staley, Kevin J.
Format: Article
Language:English
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Summary:Objectives High levels of expression of the Na+‐K+‐2Cl− (NKCC1) cotransporter in immature neurons cause the accumulation of intracellular chloride and, therefore, a depolarized Cl− equilibrium potential (ECl). This results in the outward flux of Cl− through GABAA channels, the opposite direction compared with mature neurons, in which GABAA receptor activation is inhibitory because Cl− flows into the cell. This outward flow of Cl− 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− flux and causes a more negative GABA equilibrium potential (EGABA) in immature neurons. We therefore tested whether bumetanide enhances the anticonvulsant action of phenobarbital in the neonatal brain Methods Recurrent seizures were induced in the intact hippocampal preparation in vitro by continuous 5‐hour exposure to low‐Mg2+ solution. The anticonvulsant efficacy of phenobarbital, bumetanide, and the combination of these drugs was studied Results 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% Interpretation Thus, alteration of Cl− 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
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.21229