Abstracts

Immature brain differs from mature in the development and propagation of seizures. Although the long-term sequelae of status epilepticus (SE) is more severe in mature rats, we have shown that immature rats do sustain brain damage and can develop chronic epilepsy as a result of SE. Here we studied the effect of treatment with topiramate (TPM) on the acute seizures and on the development of epilepsy in P15 rats.
24hrs after lithium pretreatment (3meq/kg,i.p.), tripolar electrodes were implanted under halothane anesthesia in P15 rats. 2hrs later, pilocarpine (PC) (60 mg/kg,s.c.) was administered. We injected TPM (10 mg/kg,i.p.) at 20,40 and 70 min after PC injection, together with atropine sulfate (ATR) (10 mg/kg,i.p.) to block cholinergic activity. Controls received no treatment or ATR alone at 70 min after PC. A group of pups was observed for 24 hours and we measured time of disappereance of SE, cumulative seizure time, duration of SE after PC injection, and spike frequency. A second group of animals subjected to SE at P15 was used for the chronic study. Three months after SE skull electrodes were implanted, and after 1-week recovery, animals were monitored by telemetry-videotape for 1 week. All measures were analyzed using Harmonie Software.
PC produced electrographical SE with quasi-continuous polyspikes. Time of disappearance of SE after treatment was significantly shorter in all TPM groups (84[plusmn] 23 min for 20 min., 59[plusmn] 23 min for 40 min and 42[plusmn] 26 min for 70 min. group), and in the ATR group (56[plusmn] 20 min) when compared to the untreated SE group (336[plusmn] 44 min). Cumulative seizure time was significantly longer in the untreated SE group (328.4[plusmn] 27.5 min) in comparison to TPM-treated groups (147[plusmn] 49 min; 115[plusmn] 27 min and 92[plusmn] 57 min respectively) and the ATR group( 125[plusmn] 35 min). The duration of SE, the number of recurrent seizures and the spike frequency were similar in all groups. All unmedicated animals developed chronic epilepsy following SE at P15. Seizure frequency in adulthood was 4.7[plusmn] 2.8 seizures/day for animals subjected to SE with no treatment, which differed significantly from the group treated at 70 min with TPM (0.1[plusmn] 0.1 seizures/ day). No animals treated with TPM at 20 or 40 min. developed epilepsy. Spike frequency was 43[plusmn] 18 spikes/hr in untreated SE group; 26[plusmn] 7 spikes/hr in rats treated at 70 min with TPM; 26[plusmn] 12 spikes/hr after TPM treatment at 40 min; and 14[plusmn] 6 spikes/hr in 20 min TPM group, which differed significantly from untreated SE group. Spike frequency in the ATR group was 29[plusmn] 4 spikes/hr.
We show that while both TPM and ATR significantly shortened the acute seizures in SE, only TPM protected immature rats from developing chronic epilepsy. These data suggest that treatment with TPM during SE in the young can protect the brain from the long-term consequences of SE, possibly through neuroprotective effects.
[Supported by: VA Research Service, by research grant NS13515 from NINDS and by a grant Johnson [amp] Johnson, Pharmaceutical Research and Development.]