Transient ischemia facilitates neuronal chloride accumulation and severity of seizures

OBJECTIVE: Preceding oxygen glucose deprivation (OGD) and ongoing seizures have both been reported to increase neuronal chloride concentration ([Cl(−)](i)), which may contribute to anticonvulsant failure by reversing the direction of chloride currents at inhibitory GABA(A) synapses. METHODS: The effects of OGD on [Cl(−)](i), seizure activity, and anticonvulsant efficacy were studied in a chronically epileptic in vitro preparation. RESULTS: Seizures initially increased during OGD, followed by suppression. On reperfusion, seizure frequency and [Cl(−)](i) progressively increased, and phenobarbital efficacy was reduced. Bumetanide (10 μmol/L) and furosemide (1 mmol/L) prevented or reduced the OGD induced [Cl(−)](i) increase. Phenobarbital efficacy was enhanced by bumetanide (10 μmol/L). Furosemide (1 mmol/L) suppressed recurrent seizures. INTERPRETATION: [Cl(−)](i) increases after OGD and is associated with worsened seizure activity, reduced efficacy of GABAergic anticonvulsants, and amelioration by antagonists of secondary chloride transport.