Can gap-junction blockade preferentially inhibit neuronal hypersynchrony vs. excitability?
Epileptic activity involves a hypersynchronous firing of large populations of brain neurons, some of which are hyperexcitable. This study explored to what extent gap-junction blockade inhibits neuronal synchronization vs. neuronal excitability. We investigated the effects of the gap-junction blockers (GJBs) 1-heptanol, 1-octanol and carbenoxolone vs. the loop diuretic furosemide on spontaneous and evoked epileptiform field potentials, induced in CA3 area of rat hippocampal slices by a 'high K(+)-low Ca(2+)' perfusion fluid. This milieu induced frequent (>30 min(-1)) spontaneous bursts, led single fimbrial stimuli to evoke repetitive population spikes (PSs), and increased PS amplitudes. Both furosemide and the three GJBs gradually reduced spontaneous field bursting, or even stopped it within one hour. The anti-bursting activity of carbenoxolone showed dose-response dependence in the concentration range 50-400 microM. 1-heptanol and 1-octanol markedly and similarly depressed all the epileptiform markers of the evoked responses, whereas carbenoxolone did not reduce the number of repetitive PSs evoked by single stimuli. By its minor effect on evoked responses, carbenoxolone resembled furosemide, rather than its congeners GJBs. These results favor the possibility that selective gap-junction blockade might antagonize epileptic synchronization, without depressing neuronal excitability.
Margineanu
D G
DG
Research & Development, Preclinical CNS Research Group, UCB S.A. Pharma Sector, Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium. doru.margineanu@ucb-group.com
Klitgaard
H
H
D020003:1-Octanol / Q000494:pharmacology; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects; D005665:Furosemide / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects*; D019850:Heptanol / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004232:Diuretics; D005665:Furosemide; D019850:Heptanol; D002229:Carbenoxolone; D020003:1-Octanol