Abstracts

RATIONALE: The 6 Hz seizure model is an alternative electroshock paradigm that utilizes a low-frequency, long duration stimulus. The resulting seizure involves a minimal clonic phase followed by stereotyped automatistic behaviors that are similar to the aura of human patients with partial or limbic epilepsy. Seizure-induced c-Fos immunoreactivity following 6 Hz seizures demonstrates that neuronal activation is limited to limbic brain structures (Epilepsia 41:(S7) 52, 2000). This study extends the previous findings by assessing the effects of two standard AEDs on neuronal activation following 6 Hz induced seizures, as measured by c-Fos immunohistochemistry.
METHODS: Psychomotor seizures were induced in CF-1 mice via corneal stimulation at 6 Hz, 3 s duration, 32 mA. Phenytoin (PHT; 40 mg/kg) or ethosuximide (ESM; 300 mg/kg) were administered (i.p.) to animals prior to 6 Hz stimulation. Control mice received either saline injection or drug injection followed by sham corneal stimulation. Mice were sacrificed 2 h after experimental treatment and transcardially perfused with 4% paraformaldehyde. The brains were removed, sliced into 50[mu]M coronal sections and processed for c-Fos immunohistochemistry.
RESULTS: At a stimulus intensity of 32 mA, PHT treatment results in 52% protection. Those animals protected with PHT treatment did not display seizure-induced c-Fos immunoreactivity in the piriform cortex and amygdala. PHT treated animals that were not protected displayed intense unilateral c-Fos immunoreactivity in the piriform cortex and amygdala. Although ESM treatment resulted in 100% protection, intense unilateral c-Fos immunoreactivity in the piriform cortex and amygdala was observed.
CONCLUSIONS: Previous studies demonstrated that the 6 Hz seizure results in intense seizure-induced c-Fos immunoreactivity in the piriform cortex and amygdala. In this study, PHT-protected animals displayed no induction of c-Fos in these limbic structures further confirming their involvement in the 6 Hz seizure. Furthermore, the PHT results suggest that unilateral neuronal activation is sufficient for seizure expression. In contrast, ESM was able to block the behavioral seizure without affecting unilateral c-Fos staining of the piriform cortex and amygdala. This phenomenon may be due to the ability of ESM to raise the threshold without affecting focal limbic activation. The effect of AED treatment on c-Fos immunoreactivity in this seizure model is presently being evaluated at a higher (44mA) stimulus intensity.
Support: NIH Grant N01-NS-42311, AFPE Pre-Doctoral Fellowship (BDK).