Although epidemiological studies have provided valuable perspectives on temporal lobe epilepsy, the ethical limitations of human research prevent a definitive answer to the important question: is antiepileptic drug (AED) therapy purely symptomatic, or does it affect the natural history of the epilepsy? The proposed experiments use an animal model of temporal lobe epilepsy to determine whether spontaneous epileptic seizures damage the brain and increase the likelihood of more seizures (i.e., promote epileptogenesis), and conversely, whether decreasing the number of seizures with AEDs significantly reduces brain damage and epileptogenesis. The central hypothesis is that prolonged treatment with an AED, which significantly reduces spontaneous epileptic seizures, causes long-term reductions in the frequency and severity of subsequent epileptic seizures after AED withdrawal. The kainate-treated rat, a well-characterized animal model of temporal lobe epilepsy, will be used to determine whether the progressive increase in the frequency of spontaneous seizures during the months after status epilepticus continues to damage the hippocampus and contributes to epileptogenesis. AEDs (i.e., phenytoin, phenobarbital, and valproate) will be used to block spontaneous epileptic seizures for prolonged periods to determine whether AED therapy reduces epileptogenesis and results in a long-term decrease in spontaneous seizure frequency (i.e., a decrease in frequency that persists after the AED therapy has been withdrawn). A related hypothesis is that prolonged AED treatment reduces neuronal death and other potential markers of hippocampal epileptogenesis. Chronic recording of electrographic seizures, quantitative histopathological studies, and in vitro electrophysiological recording of synaptic and epileptiform events in hippocampal slices will be used to determine if prolonged AED treatment decreases neuronal damage, reorganization of neural circuits, and epileptogenesis. These experiments will provide precise and valuable information regarding the influence of seizure frequency on brain damage and on the propensity for future seizures, which will be important for understanding the mechanisms of epileptogenesis and for making clinical decisions regarding AED therapy and epilepsy surgery.
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