Abstracts

RATIONALE: This study will evaluate the neuroprotective and antiepileptogenic effects of topiramate in the pilocarpine model of status epilepticus (SE). SE is a major medical and neurological emergency associated with neuronal injury and the development of epilepsy. Development of anticonvulsant agents that not only treat seizure activity, but are also neuroprotective and antiepileptogenic in treating SE would have a significant impact on the treatment of this condition.
METHODS: The pilocarpine model of SE was used to evaluate the effects of topiramate (TPM) as a neuroprotective and antiepileptogenic agent in SE. SE was induced by pilocarpine injections, terminated with diazepam and animals were evaluated for the development of spontaneous recurrent seizure activity by extensive EEG and video monitoring ( Brain Research 782: 240-247, 1998 ). Monitoring was performed at 3-6 months after the initial episode of SE. TPM was administered IP in different doses after one hour of SE and qd for four additional days. Following monitoring and analysis animals were perfused, sacrificed, and the brains removed for paraffin embedding and sectioning. Hippocampal cell counts were employed to evaluate neuronal cell loss. All studies were performed under the guidelines of VCU animal care approved protocols.
RESULTS: TPM was found to be neuroprotective in a dose dependent manner. TPM administered following 1 hour of SE and in the acute 4 day follow up time period was effective in preventing CA1 neruonal cell loss. TPM reduced cell loss from 10.3% in the epileptic animals to the baseline cell counts of sham controls. This neuroprotective effect was statistically significant. TPM in a dose dependent manner also produced a statistically significant reduction in the development of spontaneous recurrent seizures following SE. TPM was effective in reducing the the number of animals that developed epilepsy by over 60% in comparison to vehicle control animals. The minimal effective dose of TPM for producing antiepileptogenic effects was 30 mg/kg IP.
CONCLUSIONS: The data from this study demonstrate that TPM has both neuroprotective and antiepileptogenic effects following SE and suggest that this agent may be useful in decreasing the morbidity and motatily associated with SE. The results suggest that TPM may have a direct effect in preventing or inhibiting epileptogenesis in this model. The development of novel therapeutic agents for treating some of the long term effects of SE may have an important impact in improving the clinical outcome following this major neurological emergency.
[Supported by: NIH RO1-NS23350 and Johnson and Johnson Pharmaceutical Research and Development, LLC.]