title: Excitatory effects of gap junction blockers on cerebral cortex seizure-like activity in rats and mice.
abstract: OBJECTIVE
  The role of gap junctions in seizures is an area of intense research. Many groups have reported anticonvulsant effects of gap junction blockade, strengthening the case for a role for gap junctions in ictogenesis. The cerebral cortex is underrepresented in this body of research. We have investigated the effect of gap junction blockade on seizure-like activity in rat and mouse cerebral cortex slices.
  
  
  METHODS
  Seizure-like activity was induced by perfusing with low-magnesium artificial cerebrospinal fluid. The effect of three gap junction blockers was investigated in rat cortical slices; quinine (200 and 400 microm), quinidine (100 and 200 microm), and carbenoxolone (100 and 200 microm). In addition, the effect of mefloquine was investigated in wild-type mice and connexin36 knockout mice. The data were analyzed for the effect on frequency and amplitude of seizure-like events.
  
  
  RESULTS
  Paradoxical excitatory effects on seizure-like activity were observed for all three agents in rat cortical slices. Quinine (200 microm) and carbenoxolone (100 microm) increased both the frequency and amplitude of seizure-like events. Quinidine (100 microm) increased the frequency of events. Higher doses of quinine (400 microm) and carbenoxolone (200 microm) had biphasic excitatory-inhibitory effects. Similar excitatory effects were observed in adult wild-type mouse cortical slices perfused with mefloquine (5 microm or 10 microm), but were absent in slices from connexin36-deficient mice.
  
  
  CONCLUSIONS
  In conclusion, we have shown a paradoxical proseizure effect of pharmacologic gap junction blockade in a cortical model of seizure-like activity. We suggest that this effect is probably due to a disruption of inhibitory interneuron coupling secondary to connexin36 blockade.
authors.affiliation: Department of Anesthesiology, Waikato Clinical School, University of Auckland, Waikato Hospital, New Zealand. vossl@waikatodhb.govt.nz
authors.forename: Logan J
authors.initials: LJ
authors.lastname: Voss
authors.forename: Gregory
authors.initials: G
authors.lastname: Jacobson
authors.forename: James W
authors.initials: JW
authors.lastname: Sleigh
authors.forename: Alistair
authors.initials: A
authors.lastname: Steyn-Ross
authors.forename: Moira
authors.initials: M
authors.lastname: Steyn-Ross
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D013997:Time Factors; D000097004:Gap Junction delta-2 Protein
chemical_list: D018712:Analgesics, Non-Narcotic; D002229:Carbenoxolone; D017630:Connexins; D004791:Enzyme Inhibitors; D008274:Magnesium; D011802:Quinidine; D011803:Quinine; D000097004:Gap Junction delta-2 Protein