Abstracts

RATIONALE: Many genetic and pharmacological models of absence epilepsy exist, but few studies specifically report the characteristics and effects of absence status epilepticus (SE) in animal models. We studied the behavioral and electroencephalographic properties of a rodent model of absence SE, using repetitive subconvulsive doses of pentylenetetrazol (PTZ), and examined the longer-term electrophysiological and histological consequences of absence SE.
METHODS: Adult Sprague-Dawley rats were monitored for seizures behaviorally using a 5-stage modified-Racine rating scale and electrographically with 4 channel EEG. To induce absence SE, we modified the method of Nehlig et al. used to produce convulsive SE. After an initial i.p. injection of 25 mg/kg PTZ, additional doses of 10 mg/kg PTZ were given at successive 10 minute intervals, unless a stage 3 seizure occurred within the previous 10 minutes or until recurrent seizure activity occurred for 1 hour. Controls groups included rats injected with saline or a single 25 mg/kg dose of PTZ. One week later, the response to a single 25 mg/kg dose of PTZ was tested and markers of neuronal injury (Fluro-Jade) were assayed.
RESULTS: A single 25 mg/kg dose of PTZ produced a relatively brief (~1 hour) period of short (1-3 sec), infrequent ([lt]5 seconds of SWD/min) absence-like seizures, characterized by transient behavioral arrest and generalized 6-8 Hz spike-wave discharges (SWD), between which there was recovery to behavioral and electrographic baseline. Multiple timed PTZ injections of 65-85 mg/kg total over 1 hour produced a prolonged 3-4 hour period of frequent (~20 seconds SWD/min) repetitive non-convulsive seizures, characterized primarily by prolonged periods of behavioral arrest (stage 1) without recovery to behavioral or electrographic baseline between seizures. Intermittent myoclonus (stage 2) or rare ([lt]3 per total SE episode), brief ([lt]60 sec) clonic seizures without loss of posture (stage 3) could occur during the first hour only, but tonic-clonic seizures (stage 4 or 5) never occurred using this method. One week later, the electroencephalographic response to a single injection of 25 mg/kg PTZ was enhanced in rats that had a prior episode of non-convulsive SE compared to naive rats. However, there was no overt evidence of neuronal injury or death on preliminary histological analysis.
CONCLUSIONS: Prolonged (e.g. several hour) periods of generalized non-convulsive SE can be induced using repetitive carefully-timed injections of low dose PTZ. This animal model can be used to study the characteristics and effects of absence SE. Preliminary evidence suggests that a single episode of absence SE can induce a rapid kindling-like effect, but does not cause overt cell death.
Support: NIH NSADA 5K12NS0169004