Rational Polypharmacy: When Two Old Drugs Are Better Than One

Dzhala VI, Brumback AC, Staley KJ. Ann Neurol 2008;63(2):222–235. 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‐Mg 2+ 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.