A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus

Abstract

Three different classes of NMDA receptor antagonists were compared for their effectiveness in terminating prolonged status epilepticus (SE), induced by continuous hippocampal stimulation. Animals were treated after 150 min of SE by intraperitoneal administration of increasing doses of 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), MK-801 (dizocilpine), ifenprodil, or saline. EEG recordings were used to determine seizure termination. The first experiment (n = 57 animals) determined the most effective anticonvulsant dose of each agent by determining its ability to terminate SE within the next 300 min. Five control rats treated with normal saline after 150 min of SE continued to exhibit continuous seizures for the next 300 min. All drugs were administered after 150 min of SE. CPP terminated seizures with an ED 50 of 6.4 mg/kg; the maximal effective dose was 15 mg/kg. MK-801 has an ED 50 of 1.4 mg/kg; the maximal effective dose was 2 mg/kg. Ifenprodil was maximally effective at 30 mg/kg. However, an ED 50 could not be calculated. In a subsequent experiment, the NMDA antagonists were compared for their ability to terminate prolonged SE within 60 min of their administration at the most effective dose. MK-801 (2.0 mg/kg) terminated SE in 6 of 10 animals within 60 min, CPP (15 mg/kg) terminated it in 1 of 9 animals; ifenprodil (30 mg/kg) did not terminate it in any of 9 animals treated. In the 300 min following administration, CPP (6/9) and MK-801 (6/10) were equally efficacious in terminating SE but ifenprodil (2/7) was less effective (P = 0.065, chi-square test). The results indicate that the non-competitive NMDA receptor antagonist MK-801 was superior to the competitive antagonist CPP and the pH-sensitive site antagonist ifenprodil, in terminating prolonged experimental SE.

Status epilepticus: a modern approach to management

“…Limited data are available on the use of this infusion therapy in humans, although its use in RSE has theoretic advantages, there is evidence that excessive NMDA excitatory receptor-mediated transmission is an important mechanism of persistent neuronal firing in the setting of downregulation of gaminobutyric acid receptors. The evidence for efficacy of ketamine is largely anecdotal [60]. The reported adverse effects relate to its use as an analgesic, where hallucinations and other transient psychotic sequelae are reported.…”

Influence of NR2B-Selective NMDA Antagonist on Lindane-Induced Seizures in Rats

“…In addition, ifenprodil blocks the Nand P-type voltage-dependent Ca 2+ channels [32] . The anticonvulsive activity of ifenprodil has been shown in several experimental models of epilepsy like amygdale-kindled rats [19] and prolonged status epilepticus [17] . Wang and Bausch [16] observed that the electrical discharges induced by bicuculin (GABA antagonist) in a hippocampal in vitro culture could be inhibited by ifenprodil.…”

“…in a volume of 0.5 ml/kg rat body weight. The ifenprodil doses and the time of administration were chosen according to previous researches [17,18] . Lindane, DMSO and ifenprodil are produced by Sigma-Aldrich Chemical Co., USA.…”

“…It has been reported that ifenprodil was neuroprotective both in vitro and in in vivo models of a variety of neurological disorders and brain injuries, lacking many of the side effects associated with the non-subunit-selective NMDA receptor antagonists [13][14][15] . Antiepileptic properties of ifenprodil have also been suggested [16][17][18][19] . However, the effects of ifenprodil on lindane-induced seizures are still unknown.…”

Treatment of Acute Seizures and Status Epilepticus

“…Ketamine is used in the same fashion as other coma-inducing agents; that is, IV bolus, followed by maintenance infusion. The evidence for efficacy of ketamine is largely anecdotal [47,81].…”