Abstracts

RATIONALE: Status epilepticus (SE) is a medical emergency with a high risk of mortality, cognitive decline, and epileptogenesis. About 40% of SE is resistant to the fist line treatments and the risk of poor prognosis increases with a prolongation of SE. This creates a need for the development of compounds that rapidly discontinue SE. Here, we describe the effect of a novel systemically administered AMPA antagonist, NS1209, on electrographic and behavioral SE activity in rats.
METHODS: Self-sustained status epilepticus was induced by electrically stimulating the lateral nucleus of amygdala of adult Spraque-Dawley rats (n=22) for 20-30 min (100 ms train of 1-ms, 60 Hz bipolar pulses, 400 [mu]A, every 0.5 sec). For intravenous (i.v.) drug-administration, a polyethylene cannula was inserted into the right jugularis vein 1 d before induction of SE. Five rat groups were treated with various doses of NS1209 (10 - 100 mg/kg i.v. or i.p. bolus continued with an i.v. infusion of 4 - 30 mg/kg/h for 2- 24 h) 3 hours after the beginning of SE. To assess the effect of NS1209 on SE activity, rats were monitored with a continuous (24h/day) video-EEG monitoring for 3 days to assess the occurrence of high-amplitude and frequency discharges (HAFDs) during SE which are typically associated with behavioral seizures.
RESULTS: Administration of 10 mg/kg bolus (i.p.) followed with a 4 mg/kg/h infusion (i.v.) of NS1209 completely stopped the HAFDs in 50% (4/8) of the animals in 122 [plusminus] 74 minutes. A 50 mg/kg bolus (i.v.) with a 5 mg/kg/h infusion (i.v.) stopped the HAFDs as well as all epileptiform activity in 4/6 (67%) animals in 14 [plusminus] 5 minutes without recurrence. The 2 remaining rats a very few HAFDs 12 [plusminus] 11 during the next 72 hours. Administration of 100 mg, 75 mg or 50 mg bolus with 30 mg/kg/h i.v. infusion increased the mortality (7/8 died compared to 0/14 treated with doses described above, P[lt]0.001, Pearson Chi-Square-test).
CONCLUSIONS: Systemic administration of NS1209 as long as 3 h after the beginning of SE effectively stopped both the behavioural and electrographic SE activity. At optimal treatment regimen, response was obtained within 15-20 minutes without recurrence or mortality. These data show that AMPA receptor blockage may provide a novel and efficient target for the treatment of SE.
[Supported by: The Sigrid Juselius Foundation, The Vaajasalo Foundation and The Academy of Finland.]