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 furos emide, bumetanide and ethacrynic acid, which block the KCC1 potassium-chlor ide 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 suscep tibility by exposure to loud noise (an alarm bell) for 60 s. Sound exposure s were repeated at intervals to determine the time course of the seizure su ppression effect. All three loop diuretics suppressed sound-triggered seizu res in post-ischemic rats tested 2 days to 4 weeks after the ischemic expos ure. Furosemide 200 mg/kg had no effect in 4/4 rats made acutely audiogenic seizure-prone by infusion of bicuculline into the inferior colliculus, ind icating that the effect was not due to general anti-seizure activity. Manni tol 2 mg/kg had no effect in 6/6 post-ischemic rats, indicating that the ef fect was not due to diuresis or fluid shifts. These results are consistent with the hypothesis that the exposure to global ischemia caused an upregula tion of the potassium-chloride transporter KCC2 in neurons which persisted for at least 4 weeks. (C) 2000 Elsevier Science B.V. All rights reserved.