Antiepileptic effect of gap-junction blockers in a rat model of refractory focal cortical epilepsy.
OBJECTIVE
Epilepsy is the most common serious neurologic disease, and current treatments are ineffective for <or=30% of patients. Gap junctions have been implicated in seizure generation and propagation, and as such, may represent a novel therapeutic target but have been little investigated in vivo. We set out to assess the efficacy and tolerability of gap-junction blockers delivered to the seizure focus in a well-characterized model of refractory cortical epilepsy in rats.


METHODS
A chronic epilepsy focus was induced in the cortex of rats by using tetanus toxin, and subsequent studies were conducted in freely moving unanesthetized animals with frequent spontaneous seizures, as we previously described. Carbenoxolone, meclofenamic acid, and saline were applied directly to the seizure focus. EEG, electromyogram (EMG), and behavioral parameters were measured for >or=1 h before drug infusion and for >or=3 h afterward. No ill effects were observed.


RESULTS
An immediate and marked reduction in percentage of seizure time was seen in rats receiving carbenoxolone (baseline, 69.4%+/- 7.0% (SEM); maximum effect, 9.3%+/- 3.5%, p <or=0.001) and meclofenamic acid (baseline, 58.3%+/- 3.7%; maximum effect, 0.92%+/- 0.92%, p < 0.001). No effect was seen after saline infusion.


CONCLUSIONS
Gap-junction blockers applied focally are effective at suppressing seizures and, as such, represent a potential new treatment for epilepsy. Development of focal treatment strategies is essential in this regard.
Nilsen
Karen E
KE
Epilepsy Group, Centre for Clinical Neurosciences, St. Georges, University of London, London, England.
Kelso
Andrew R C
AR
Cock
Hannah R
HR
D000287:Administration, Topical; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002229:Carbenoxolone / Q000008:administration & dosage / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology*; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D004351:Drug Resistance; D004569:Electroencephalography / Q000187:drug effects / Q000706:statistics & numerical data; D004576:Electromyography / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D007260:Infusion Pumps; D015552:Injections, Intralesional; D008469:Meclofenamic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*; D013238:Stereotaxic Techniques; D013744:Tetanus Toxin
D000927:Anticonvulsants; D017630:Connexins; D013744:Tetanus Toxin; D008469:Meclofenamic Acid; D002229:Carbenoxolone