Abstracts

High expression level of the Na⁺[ndash]K⁺[ndash]2Cl^[ndash] (NKCC1) co-transporter in immature neurons causes the accumulation of chloride ions and a depolarized Cl^[ndash] equilibrium potential (E[sub]Cl[/sub]). This is linked to a higher seizure propensity and poor EEG response in neonates to the barbiturates and benzodiazepines, conventional anticonvulsant drugs that target Cl^[ndash][ndash]permeable GABA[sub]A[/sub] receptor operated channels. We tested the hypothesis that pharmacological blocking of the NKCC1 by bumetanide may enhance the anticonvulsant action of phenobarbital by alteration of Cl^[ndash][ndash]transport., We performed extracellular field potential recordings of multiple unit activity and population field activity in the intact hippocampal preparations [italic]in vitro[/italic] from male Sprague Dawley rats at postnatal day 4 (P4) to P6. Recurrent tonic-clonic seizures were induced by low[ndash]Mg⁺ ACSF. Drugs were applied during 120 min after 6-9 recurrent tonic-clonic seizures. Their efficiency to suppress seizures was studied., Continuous superfusion of low[ndash]Mg²⁺ ACSF induced recurrent tonic-clonic seizures increasing in frequency and power. Phenobarbital (100 [mu]M) decreased seizure frequency by 37 % or abolished them in 28 % preparations. Bumetanide (10 [mu]M) reduced seizure frequency by 46 % or abolished them (25 %). Bumetanide in combination with phenobarbital reduced seizure frequency by 75% or completely suppressed its expression in 72 % preparations., Alteration of Cl^[ndash][ndash]transport by bumetanide enhances anticonvulsant action of phenobarbital. Our results suggest a potential use of bumetanide in combination with GABA-enhancing anticonvulsants to improve the therapy of early-life seizures., (Supported by US National Institutes of Health and National Institute of Neurological Disorders and Stroke grants.)