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Bumetanide enhances phenobarbital efficacy in a neonatal seizure model.

Author(s): Dzhala VI, Brumback AC, Staley KJ

Affiliation(s): Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Publication date & source: 2008-02, Ann Neurol., 63(2):222-35.

Publication type: Research Support, N.I.H., Extramural

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 (E(Cl)). This results in the outward flux of Cl- through GABA(A) channels, the opposite direction compared with mature neurons, in which GABA(A) 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 (E(GABA)) 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.

Page last updated: 2008-06-22

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