Agents which block potassium-chloride cotransport prevent sound-triggered seizures in post-ischemic audiogenic seizure-prone rats

The purpose of this study was to determine whether the loop diuretics furosemide, bumetanide and ethacrynic acid, which block the KCC1 potassium-chloride transporter in the kidney loop of Henle and the KCC2 potassium-chloride transporter in neuronal membranes, would prevent sound-triggered seizures in post-ischemic audiogenic seizure-prone rats. The rats were infused with the test agent via tail vein shortly before being tested for seizure susceptibility by exposure to loud noise (an alarm bell) for 60 s. Sound exposures were repeated at intervals to determine the time course of the seizure suppression effect. All three loop diuretics suppressed sound-triggered seizures in post-ischemic rats tested 2 days to 4 weeks after the ischemic exposure. Furosemide 200 mg/kg had no effect in 4/4 rats made acutely audiogenic seizure-prone by infusion of bicuculline into the inferior colliculus, indicating that the effect was not due to general anti-seizure activity. Mannitol 2 mg/kg had no effect in 6/6 post-ischemic rats, indicating that the effect was not due to diuresis or fluid shifts. These results are consistent with the hypothesis that the exposure to global ischemia caused an upregulation of the potassium-chloride transporter KCC2 in neurons which persisted for at least 4 weeks. (C) 2000 Elsevier Science B.V. All rights reserved.