Abstracts

Rationale: Today preclinical epilepsy research is shifting towards the use of true epilepsy models to unravel the processes underlying epileptogenesis. One of the most widely used and thus best characterized animal models for temporal lobe epilepsy is the kainic acid-induced post-status epilepticus rat model. In rodents status epilepticus (SE) is followed by a latent phase during which the brain is rendered epileptic. Eventually, the animals develop chronic spontaneous seizures. In order to generate reproducible conditions between rats, the induced SE should be interrupted after 90 minutes. There is consensus that this time interval is sufficient to initiate epileptogenesis and that this approach limits animal suffering. Most research groups use systemic administration of 10 mg/kg diazepam as a standard protocol to interrupt SE. Termination of behavioral seizure activity is currently used by many researchers as a parameter to monitor the establishment of SE control. We aim to optimize the standard protocol to control kainic acid-induced SE using electrocorticographic (ECoG) monitoring. This technique enables us to unambiguously verify whether lack of behavioral seizure activity is indeed always correlated with full SE control. Methods: SE was induced in rats by consecutive intraperitoneal kainic acid injections (5 mg/kg) every hour. Using simultaneous video-ECoG telemetry monitoring establishment of SE was verified behaviorally and electrocorticographically. Diazepam (10 mg/kg and 20 mg/kg) or a mixture of diazepam and ketamine (10 mg/kg : 50 mg/kg and 20 mg/kg : 50 mg/kg) was administered intraperitoneally to establish SE termination after 90 minutes. Results: Behaviorally, all rats consistently appeared to be seizure free irrespective of the administration of diazepam alone or in combination with ketamine. However, this was not confirmed by the ECoG analysis. SE was controlled electrocorticographically in only 28 % of the rats after 10 mg/kg diazepam administration (n=7). In the non-responders, ECoG activity showed continued epileptic activity without typical seizure-related behavioral activity after pharmacological intervention. A combination of 20 mg/kg diazepam and 50 mg/kg ketamine successfully inhibited all behavioral and electrocorticographical seizure activity in 100 % of the rats (n=8). Conclusions: The present data clearly demonstrate the need to use ECoG monitoring to enable reliable assessment of SE control as the number of false positives is extremely high when SE control is only behaviorally assessed. Our data show that the standard protocol to control SE (i.e. 10 mg/kg diazepam administration) is not sufficient to terminate SE in all animals and needs further optimization. We suggest a combination of 20 mg/kg diazepam and 50 mg/kg ketamine as successful treatment to control kainic acid-induced SE in rats.