Effect on Epileptogenesis of Carbamazepine Treatment During the Silent Period of the Pilocarpine Model of Epilepsy


Address correspondence and reprint requests to Dr. T. Lemos at Department of Pharmacology, Universidade Federal de Santa Catarina, R. Ferreira Lima 82, Florianopolis, SC, 88015-420, Brazil. E-mail: tlemos@mbox1.ufsc.br


Summary:  Purpose: This study addresses the question of epileptogenesis by investigating the effects of carbamazepine (CBZ) on the silent period of the pilocarpine model of epilepsy.

Methods: Adult Wistar rats were subjected to status epilepticus (SE) induced by pilocarpine and treated with CBZ or saline, i.p, during 56 days. Latency for the first spontaneous seizure, incidence, frequency, and duration of seizures were monitored for ≤56 days after treatment. Hippocampal histologic analysis was performed.

Results: CBZ reduced the frequency and duration of the seizures and the hippocampal damage.

Conclusions: CBZ did not abort the epileptogenesis but minimized the expression of seizures and hippocampal damage.

The pilocarpine model of epilepsy has been considered one of the best models to study temporal lobe epileptogenesis because it mimics the human epileptic condition. The pilocarpine paradigm can be divided into three distinct periods: (a) an acute period (24 h) after pilocarpine administration, characterized by a limbic status epilepticus (SE); (b) a silent period with a progressive normalization of EEG and behavior that lasts ∼15 days; and (c) a chronic period with spontaneous recurrent seizures (SRSs) (1,2).

Carbamazepine (CBZ), a conventional antiepileptic drug (AED), is effective against SRSs in this model (3). In this study we addressed the epileptogenesis by investigating the effects of CBZ treatment during the silent period of the pilocarpine model of epilepsy.


Adult male Wistar rats weighing 200–250 g were subjected to SE induced by pilocarpine (360 mg/kg, i.p.). Twenty-four hours after SE, animals were divided into two groups (20 rats per group). They were treated with saline or CBZ (Sigma), dissolved in Tween 80 saline solution, at dose of 40 mg/kg, 3 times/day, i.p., for 56 days.

Animal behavior was video-monitored (12 h/day) during treatment and for ≤56 days after treatment starting 24 h after the drug withdrawal. The parameters analyzed were (a) latency for the first spontaneous seizure, (b) incidence of seizures, (c) frequency, and (d) duration of seizures. At the end of the experiments, histologic analysis (Nissl staining) of the hippocampal formation was performed. Integrity of hippocampal cell layers was classified as follows: grade 0, preserved hippocampal structure; grade 1, mild damage, characterized by mild neuronal loss and gliosis with preserved general structure of hippocampal formation; grade 2, moderate neuronal loss and gliosis with deformation of some hipocampal subfields and/or dentate gyrus; and grade 3, severe neuronal loss and gliosis with a greatly shrunken and sclerosed hippocampal formation.

Significance of differences between saline and CBZ groups was calculated with the U test of Mann and Whitney in nonparametric data and Student's t test in parametric data.


The incidence of SRSs during and after treatment was 100% in the saline group and 75% in the CBZ-treated group. Eight animals from each group died during SE. The latency for the first spontaneous seizure was 17 ± 3 and 21 ± 2 days for saline and CBZ groups, respectively. Seizure frequency (mean ± SEM) was 12.8 ± 3.1 during saline treatment, 6.2 ± 1.9 during CBZ treatment, 14.5 ± 2.2 after saline treatment, and 5.8 ± 1.5 after CBZ treatment. Seizure duration (seconds, mean ± SEM) was 41.8 ± 3.1 during saline treatment, 15.72 ± 3.3 during CBZ treatment, 38.3 ± 2.1 after saline treatment, and 20.9 ± 3.2 after CBZ treatment. CBZ treatment reduced frequency and seizure duration both during and after treatment (Fig. 1). Hippocampal analysis showed moderate damage of the hippocampal formation in the CBZ-treated animals in contrast with the severe damage of the saline-treated epileptic animals (Fig. 2).

Figure 1.

Effect of carbamazepine treatment during the silent period of the pilocarpine model on frequency (A) and duration (B) of spontaneous seizures in rats. Seizures were recorded during 56 days after treatment. Data show mean ± SEM. *p < 0.05, Mann–Whitney U test. #p < 0.05, Student's t test versus saline.

Figure 2.

Nissl-stained horizontal sections through the hippocampal formation of normal rats (A) and rats with the pilocarpine model of epilepsy and treated with saline (B) or carbamazepine (C) during the silent period. Photomicrographs show (A) the integrity of a normal hippocampal formation, (B) the typical severe hippocampal sclerosis, and (C) moderate damage of this structure. ×25.


Carbamazepine is clinically effective in controlling temporal lobe seizures (4). In the pilocarpine model of epilepsy, it was previously showed that CBZ is effective against spontaneous seizures (chronic period) (2), but not in protecting animals from pilocarpine-induced SE (acute period) (5). In this study, CBZ treatment during the silent period did not abort the epileptogenesis but minimized the expression of seizures and the hippocampal damage. This indicates that in the pilocarpine model of epilepsy, prophylactic treatment could be useful to address the epileptogenesis. Further studies are necessary to quantify and clarify the observed protection. Meanwhile our data suggest that although there is no effective prophylactic treatment for epilepsy, it does not preclude some possible benefits of the treatment. This must be more intensively investigated, considering the drugs' adverse effects (6).

Acknowledgment: We thank Dr. E. Cavalheiro for support and stimulation. This study was upported in part by a grant from CNPq (Brazil)