Excitatory effects of gap junction blockers on cerebral cortex seizure-like activity in rats and mice.
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.
Voss
Logan J
LJ
Department of Anesthesiology, Waikato Clinical School, University of Auckland, Waikato Hospital, New Zealand. vossl@waikatodhb.govt.nz
Jacobson
Gregory
G
Sleigh
James W
JW
Steyn-Ross
Alistair
A
Steyn-Ross
Moira
M
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
D018712:Analgesics, Non-Narcotic; D002229:Carbenoxolone; D017630:Connexins; D004791:Enzyme Inhibitors; D008274:Magnesium; D011802:Quinidine; D011803:Quinine; D000097004:Gap Junction delta-2 Protein