Submitted on July 11, 2008
Revised on March 10, 2009
Accepted on March 10, 2009
Bumetanide, an NKCC1 Antagonist, Does Not Prevent Formation of Epileptogenic Focus but Blocks Epileptic Focus Seizures in Immature Rat Hippocampus
Romain Nardou1, Yehezkel Ben-Ari2*, and Ilgam Khalilov3
1 INMED-INSERM U 901
2 INMED-INSERM U901
3 INSERM U901
* To whom correspondence should be addressed. E-mail: ben-ari{at}inmed.univ-mrs.fr.
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 (DFGABA ) 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 DFGABA 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 DFGABA in epileptic neurons.
