Bumetanide, an NKCC1 antagonist, does not prevent formation of epileptogenic focus but blocks epileptic focus seizures in immature rat hippocampus.
Excitatory GABA action induced by high [Cl(-)](i) is thought to contribute to seizure generation in neonatal neurons although the mechanism of this effect remains unclear. We report that bumetanide, a NKCC1 antagonist, reduces driving force of GABA-mediated currents (DF(GABA)) in neonatal hippocampal neurons and blocks the giant depolarizing potentials (GDPs), a spontaneous pattern of network activity. In the preparation composed of two intact interconnected hippocampi, bumetanide did not prevent generation of kainate-induced seizures, their propagation to the contralateral hippocampus, and formation of an epileptogenic mirror focus. However, in the isolated mirror focus, bumetanide effectively blocked spontaneous epileptiform activity transforming it to the GDP-like activity pattern. Bumetanide partially reduced DF(GABA) and therefore the excitatory action of GABA in epileptic neurons. Therefore bumetanide is a potent anticonvulsive agent although it cannot prevent formation of the epileptogenic mirror focus. We suggest that an additional mechanism other than NKCC1-mediated contributes to the persistent increase of DF(GABA) in epileptic neurons.
Nardou
Romain
R
Institut de Neurobiologie de la Mediterranee, Institut National de la Santé et de la Recherche Médicale Unité 901, 13273 Marseille Cedex 09, France.
Ben-Ari
Yehezkel
Y
Khalilov
Ilgam
I
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D001703:Biophysics; D002034:Bumetanide / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D007839:Functional Laterality; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D007608:Kainic Acid; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D013057:Spectrum Analysis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018683:Excitatory Amino Acid Agents; D018756:GABA Antagonists; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D007608:Kainic Acid; D001640:Bicuculline