Time-dependent decrease in the effectiveness of antiepileptic drugs duringthe course of self-sustaining status epilepticus

An animal model of self-sustaining status epilepticus (SSSE) induced in rat s by brief intermittent perforant path stimulation (PPS) was examined with regard to the effects of two conventional antiepileptic drugs, diazepam and phenytoin. Thirty or sixty minutes PPS induced SSSE characterized by conti nuous behavioral and electrographic seizures lasting for hours. Both diazep am (10 mg/kg i.v.) and phenytoin (50 mg/kg i.v,) prevented the establishmen t of SSSE when administered 10 min prior to PPS. The injection of diazepam to seizing animals, 10 min after the end of 30 min PPS, was significantly l ess effective than pretreatment in attenuating SSSE. Administration of diaz epam after 60 min PPS was characterized by a further decrease of its effica cy. Phenytoin was effective in aborting SSSE when injected 10 min after 30 min PPS. However, its efficacy was vastly decreased if injected 40 min afte r 30 min PPS, or 10 min after 60 min PPS. It is concluded that antiepilepti c drugs, while highly effective in blocking the induction of SSSE, failed t o affect its maintenance. SSSE induced by PPS is an advantageous animal mod el of refractory status epilepticus, which may be used in preclinical studi es of novel antiepileptic drugs. (C) 1998 Elsevier Science B.V. All rights reserved.