Abstracts

RATIONALE: Refractory status epilepticus (SE)is marked by a loss of sensitivity to treatment with the non-competitive GABAA agonist, diazepam. This sensitivity can be restored, in experimental status epilepticus, by treatment with NMDA antagonists. The present studies were designed to determine whether this pharmacodynamic interaction is the result of specific receptor sytem relationships or is a more general anticonvulsant interaction. METHODS: SE was induced by injection of homocysteine thiolactone to rats with actively epileptogenic cortical cobalt lesions. Treatment consisted of ip administration of one of a variety of non-GABAergic anticonvulsants (ketamine, NPC-17742, remacemide, harkoseride or phenytoin)given at doses that did not control seizures in this model when used as monotherapy, followed by treatment with one of a variety of GABAergic anticonvulsants (diazepam, lorazepam, phenobarbital, thiopental, muscimol, propofol, or tiagabine) given at a range of doses. The median effective dose (ED50) for each GABAergic drug was calculated and compared when it was used as monotherapy and when it was used in one of the polytherapy regimens. Both motor and electrographic evidence of seizure activity were evaluated for 90 minutes after both drugs were injected. RESULTS: Initial treatment with any of the non-GABAergic anticonvulsants resulted in a 70-90% decrease in the ED50 for each of the non-competitive GABAA agonists. There was no change in the ED50 for muscimol or tiagabine. CONCLUSIONS: These results suggest that the the restoration of benzodiazepine sensitivity during status epilepticus is not the result of NMDA receptor modulation. Any treatment that causes a reduction in excitatory drive on GABAergic inhibitor neurons will potentiate the efficacy of any of the non-competitive GABAA receptor agonists, while having no effect on the sensitivity of the GABAA receptor itself to either competitive agonists or to increases in endogenous GABA at the synapse. This finding has important clinical implications, because available non-GABAergic anticonvulsants, such as fosphenytoin, could be used rationally to assist in restoration of sensitivity to benzodiazepines.