N-methyl-D-aspartate receptor activation regulates refractoriness of status epilepticus to diazepam

Status epilepticus, prolonged intermittent or continuous seizure activity l asting 30 min or longer, is associated with high morbidity and mortality, T he longer a seizure persists, the more refractory to treatment it becomes. The pilocarpine model of status epilepticus in rodents develops refractorin ess to many first-line treatments as seizure duration increases, rendering it a good model to study refractory status epilepticus. This study was init iated to study the development of refractoriness of pilocarpine-induced sta tus epilepticus to diazepam. Early pilocarpine-induced status epilepticus r esponded rapidly to diazepam treatment, whereas status epilepticus of longe r duration became increasingly less responsive to treatment. Dizocilpine ma leate-pretreated animals responded rapidly to diazepam treatment, even afte r 60 min of status epilepticus. Animals administered dizocilpine maleate at 15, 30 or 60 min after the onset of status epilepticus also demonstrated a rapid response to diazepam compared to pilocarpine-alone-treated animals. The longer the status epilepticus progressed prior to dizocilpine maleate i njection, the longer the status epilepticus lasted after diazepam treatment . However, in all cases where dizocilpine maleate was administered, one inj ection of diazepam was able to terminate the status epilepticus, in contras t to the animals that did not receive dizocilpine maleate, in which the sei zure was only attenuated. The results indicate that N-methyl-D-aspartate re ceptor activation plays a role in the seizure-induced refractoriness to ben zodiazepines in status epilepticus, and blocking N-methyl-D-aspartate recep tor activation converts refractory status epilepticus to a seizure responsi ve to benzodiazepine therapy. These findings offer insights into developing novel therapeutic interventio ns to improve the treatment of status epilepticus. Understanding the molecu lar mechanisms that mediate the effects of N-methyl-D-aspartate receptor ac tivation on the development of resistance to treatment in status epilepticu s will provide rational insights into more rapid methods to terminate seizu re activity in this condition. (C) 1999 IBRO. Published by Elsevier Science Ltd.