Excitatory effects of gap junction blockers on cerebral cortex seizure‐like activity in rats and mice

Abstract

SUMMARYPurpose: 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 lM), quinidine (100 and 200 lM), and carbenoxolone (100 and 200 lM). 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 seizurelike activity were observed for all three agents in rat cortical slices. Quinine (200 lM) and carbenoxolone (100 lM) increased both the frequency and amplitude of seizure-like events. Quinidine (100 lM) increased the frequency of events. Higher doses of quinine (400 lM) and carbenoxolone (200 lM) had biphasic excitatory-inhibitory effects. Similar excitatory effects were observed in adult wild-type mouse cortical slices perfused with mefloquine (5 lM or 10 lM), but were absent in slices from connexin36-deficient mice. Discussion: In conclusion, we have shown a paradoxical proseizure effect of pharmacologic gap junction blockade in a cortical model of seizurelike activity. We suggest that this effect is probably due to a disruption of inhibitory interneuron coupling secondary to connexin36 blockade.

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

“…Consistently, substances promoting gap junction communication by intracellular alkalinization (trimethylamine, ammonium chloride) have been found to increase epileptiform activity (K€ ohling et al, 2001;Perez-Velazquez et al, 1994). It should be noted, however, that others have reported proconvulsive effects of gap junction blockade through carbenoxolone (Voss et al, 2009). In this context one has to consider that most gap junction blockers are not specific, i.e., they have many side effects (Rozental et al, 2001) and barely discriminate between connexin isoforms and thus cell types (Giaume et al, 2010;Steinh€ auser and Seifert, 2002).…”

Role of gap junctions in epilepsy

“…In a Co 2+ epilepsy model, Mylvaganam et al demonstrated that octanol diminishes ictal and interictal discharges [79] . However, paradoxical excitatory effects of gap junction blockers on seizure-like activity induced by low Mg 2+ in rat cortical slices were recently reported by Voss et al They found that quinine and carbenoxolone increase both the frequency and the the amplitude and quinidine increases the frequency of seizure-like events [104] .…”

“…C57/BL6 wild-type and Cx36-knockout mice Mefloquine increases SLE frequency and amplitude in WT mice and (4-month-old) these effects are absent in slices from Cx36-knockout mice [104] .…”

“…Sprague-Dawley rats (5-to 8-week-old) Quinine and carbenoxolone increase both the frequency and the amplitude Neocortical slice of SLEs [104] .…”

Bridging the Gap – Understanding the Role of Gap Junctions in Seizures

“…In support of this, there are a growing number of experimental studies showing a reduction in seizure severity following pharmacological gap junction blockade (Bostanci and Bagirici 2007;Nassiri-Asl et al 2009). Intriguingly, several studies point to gap junction blockade having the opposite effect (Voss et al 2009;Jacobson et al 2010), suggesting that the relationship between gap junction regulation and seizure propensity is multifaceted. The apparent discrepancies in the literature surrounding the role of gap junctions in seizurogenesis probably reflect two main complicating factors.…”