Effects in vitro and in vivo of a gap junction blocker on epileptiform activities in a genetic model of absence epilepsy.
We investigated the effects of carbenoxolone (CBX), a gap junctions (GJ) blocker, on epileptiform activities in vivo and in vitro. In a first series of experiments, i.p. CBX decreased the cumulative duration of cortical spike-wave discharges (SWD) in adult Genetic Absence Epilepsy Rats from Strasbourg (GAERS) without reduction in the SW amplitude or frequency. Since SWD are generated in thalamocortical networks, we studied the effect of CBX on thalamic and cortical activities elicited by 4-aminopyridine (4AP) in thalamocortical slices from GAERS or non-epileptic rats (NER). Spontaneous ictal-like activities (ILA) were recorded simultaneously in thalamus and somatosensory cortex. However, experiments where these structures were surgically separated showed that ILA were generated in the cortex and recorded by volume conduction in the thalamus. GABA-dependent negative field potentials were also recorded in the cortex, either isolated or initiating ILA. After bath-applying CBX (100 microM), the frequency and cumulative duration of ILA decreased but less rapidly in GAERS than in NER slices and they disappeared at a time point when GABA-dependent negative potentials remained. These data suggest that GJ do not mediate the 4AP induced interneuronal synchronisation but may be implicated in the spreading of the synchronised activities from interneuronal networks to principal neurones. Our results show that CBX exerts an antiepileptic action in vivo, and that GJ blockers limits spread of synchronised activities in vitro. They may represent an appropriate target for development of new antiepileptic drugs.
Gigout
S
S
Neurobiologie et Pharmacologie moléculaire, INSERM U 573, 75014 Paris, France.
Louvel
J
J
Pumain
R
R
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002229:Carbenoxolone / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced; D012965:Sodium Chloride / Q000494:pharmacology; D013003:Somatosensory Cortex / Q000187:drug effects; D013787:Thalamic Nuclei / Q000187:drug effects*
D000927:Anticonvulsants; D026902:Potassium Channel Blockers; D012965:Sodium Chloride; D015761:4-Aminopyridine; D002229:Carbenoxolone