Effects of Antiepileptie Drugs on Seizure Thresholds in the Rat Kindling Model of Temporal Lobe Epilepsy

Purpose: To determine the antiepileptic profiles of antiepileptic drugs (AEDs), we compared the effects of various AEDs, including phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), and diazepam (DZP), on seizure thresholds in the rat kindling model of temporal lobe epilepsy. Methods: Male Sprague-Dawley rats were used. A tripolar electrode was implanted into the amygdala under pentobarbital anesthesia. All rats underwent daily kindling stimulation (100 Hz, 2 s) until stable generalized seizures were induced. The generalized seizure-triggering threshold (GST) was then determined for each rat by the application of stimulation, which increased in intensity by 50 μA steps at intervals of 15 min. After intraperitoneal administration of PHT (180 mg/kg), CBZ (40 mg/kg), VPA (200 mg/kg), or DZP (2 mg/kg), electrical stimulation at the intensity of the GST, or 2 or 3 times the GST, was delivered to the amygdala, and reversal of the anticonvulsant effects was measured. Results: All AEDs had potent anticonvulsant effects on amygdala-kindled seizures induced by stimulation at the GST. After treatment with PHT and CBZ, when the stimulus intensity was increased to 2 or 3 times the GST, the anticonvulsant effects were completely eliminated. In contrast, the effects of VPA were partially reversed and those of DZP were only slightly reversed by increases in the stimulus intensity. Conclusions: These findings suggest that the prinicipal mechanism for the anticonvulsant effects of PHT and CBZ, which act primarily on voltage-sensitive Na+ channels, is the significant increase of seizure thresholds in epileptogenic foci. In our previous study, lamotrigine had the same effects as PHT and CBZ on seizure thresholds. In contrast, the fundamental profile of VPA and DZP, which enhance a-aminobutyric acid (GABA)/benzodiazepine (BZD) systems, differs from that of PHT/CBZ-type AEDs, and the main mechanism for the anticonvulsant effects of these two drugs is blockade of seizure propagation and generalization. This conclusion is consistent with our recent findings for tiagabine (a selective GABA uptake inhibitor) in the kindling model (Morimoto et al. Epilepsia 1997;38:966).