Abstracts

Rationale: Cortical dysplasia (CD) has been identified as one of the most important factors underlying intractable epilepsy. In recent years, vagal nerve stimulation (VNS) has become an alternative treatment for patients resistant to medical treatment and surgery. In this study, the effects of VNS on epileptogenesis and blood-brain barrier (BBB) permeability are investigated in kindled rats with CD. Methods: The experimental groups consist of 8 Sprague-Dawley rats. Pregnant rats are exposed to abdominal gamma irradiation of 145 cGy on day 17 of pregnancy to induce CD in the offspring. Pentylenetetrazole (PTZ) is used to induce chemical kindling. Fifteen-day-old in-utero irradiated rats with CD are given a dose of 30 mg/kg PTZ intraperitoneally three times a week. After each injection, the convulsive behavior is observed for 20 min and classified according to the Racine s scale. Anesthetized rats are implanted a VNS electrode around the left vagal nerve. The stimulation of left vagal nerve is performed for 48 h at output currents of 0.5 or 1 mA (pulse duration: 0.5 ms, at 30 Hz frequency). Then intracranial EEG electrodes are placed bilaterally into the CA1 region of hippocampus of animals and animals are allowed to wake up. EEG recording starts 5 minutes before the injection of the last dose of PTZ and continues for 1 h. To assess the BBB permeability, horseradish peroxidase (HRP; 200 mg/kg, iv) is injected and the animals are perfusion fixed. The extravasation of the tracer is evaluated macroscopically in coronal brain sections that are cut by a vibratome. Samples from cerebral cortex and hippocampus are processed for electron microscopy and the ultrastructure of the brain capillaries are evaluated under a transmission electron microscope. Results: After the application of this procedure, kindled rats with CD exhibited seizures with mean Racine s scores of 3.57 1.2. Among the kindled rats with CD treated with 0.5 or 1 mA VNS, only one rat exhibited seizure activity with racine score of 2 and the rest of the animals showed no signs of seizures. The observations of seizure activity were also verified with EEG recordings. Widespread HRP reaction products were macroscopically observed mainly in the cerebral cortex and also in subcortical regions in coronal Vibratome sections of the brains of kindled rats with CD. No marked HRP reaction product was noted in coronal brain sections of kindled rats with CD treated with 0.5 or 1 mA VNS. Electron microscopic observations revealed frequent transport vesicles containing electron-dense HRP reaction products in the cytoplasm of brain capillary endothelial cells in both cerebral cortex and hippocampus of kindled animals with CD. In these animals, following the application of 0.5 or 1 mA VNS, the brain capillary endothelial cells in both cerebral cortex and hippocampus were observed to be devoid of transport vesicle containing HRP reaction products. Conclusions: The results of this study suggest that VNS inhibits seizure activity and maintains BBB integrity in the treatment of epilepsy associated with CD.