Antiepileptic Effect of Gap‐junction Blockers in a Rat Model of Refractory Focal Cortical Epilepsy

Abstract

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. 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. 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. 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.