Abstracts

RATIONALE: To assess whether treatment with Topiramate the onset of Kainic Acid (KA) induced status epilepticus modifies its long-term neurological consequences.
Prior studies have shown that KA induced status epilepticus (KA-SE) results in permanent neurological deficits including an increased susceptibility to seizures. KA-SE rats exhibit prominent neuronal degeneration in CA3, CA1 and the hilus of the dentate gyrus and have a facilitation of their kindling rate (J. Neuroscience 12: 4173-4187, 1992). Treatment with high doses of Phenobarbital (at a dose likely to block AMPA receptors) given 30 minutes after inducing KA-SE resulted in a dramatic reduction of degeneration in the hilar polymorphic neurons, decreased mossy fiber sprouting and normalized the rate of kindling. Topiramate, an AMPA-receptor antagonist and a GABA-A modulator, may have a similar effect in the KA-SE model.
METHODS: Three groups of rats were studied: normal controls, rats with status epilepticus induced with kainic acid (KA-SE rats; three hourly injections of 5mg/kg sc), and KA-SE rats that were treated after one hour of status epilepticus with twice daily doses of Topiramate (60mg/kg sc) for 3-5 days. Additional groups at 20 mg/kg and 40 mg/kg were also studied to evaluate a dose-response relationship. Several measures of neuroprotection were assessed in the three groups: 1) the extent of cell injury using Cresyl violet stain, 2) the extent of Mossy Fiber sprouting induced by kainic acid, 3) the extent of terminal degeneration with the Fink-Heimer staining, 4) the rate of perforant path kindling starting three weeks after KA-SE as one measure of late epileptogenesis, and 5) number of late spontaneous seizures ten weeks after KA-SE.
RESULTS: Topiramate given one hour after Kainic acid induced status epilepticus. In female rats, the use of Topiramate at a dose of 60 mg/kg improved survival after KA-SE despite similar behavioral seizure scores. In both males and females, Topiramate at 60mg/kg diminished the extent of neuron loss in the hilar polymorphic region and reduced the development of mossy fiber sprouting three weeks after KA-SE (n=12) as compared to KA-SE rats. (n=12). At lower doses, there was a trend for improved survival after KA-SE, more neuronal loss and mossy fiber sprouting. Prominent degeneration was observed after KA-SE in the pyramidal regions of the CA1 and CA3 regions. However, Topiramate at 60 mg/kg selectively protected the hilar polymorphic neurons.
CONCLUSIONS: Topiramate has neuroprotective properties in a dose-dependent manner in the Kainic Acid model of Status Epilepticus when given one hour after KA-SE. The clinical significance of these observations deserve further study in other experimental models of status epilepticus.
[Supported by: Johnson & Johnson Pharmaceutical Research Institute]; (Disclosure: Grant - Johnson & Johnson Research Pharmaceutical Institute; NINDS, Consulting - Ortho-McNeil Pharmaceuticals)