Chronic limbic epilepsy models for therapy discovery: Protocols to improve efficiency

Abstract

Objective There have been recommendations to improve therapy discovery for epilepsy by incorporating chronic epilepsy models into the preclinical process, but unpredictable seizures and difficulties in maintaining drug levels over prolonged periods have been obstacles to using these animals. We report new protocols in which drugs are administered through a new chronic gastric tube to rats with higher seizure frequencies to minimize these obstacles. Methods Adult rats with spontaneous limbic seizures following an episode of limbic status epilepticus induced by electrical hippocampal stimulation were monitored with long‐term video– electroencephalography (EEG). Animals with a predetermined baseline seizure frequency received an intragastric tube for drug administration. Carbamazepine, levetiracetam, phenobarbital, and phenytoin were tested with either an acute protocol (an increasing single dose every other day for a maximum of three doses) or with a chronic protocol (multiple administrations of one dose for a week). Drug levels were obtained to correlate the effect with the level. Results With the acute protocol, all four drugs induced a clear dose‐related response. Similar dose‐related responses were seen following the week‐long dosing protocol for carbamazepine, phenobarbital, and phenytoin, and these responses were associated with drug levels that were in the human therapeutic range. The response to chronic levetiracetam was much less robust. The gastric tube route of administration was well tolerated over a number of months. Significance Using rats with stable, higher seizure frequencies made it possible to identify the potential of a drug to suppress seizures in a realistic model of epilepsy with drug levels that are similar to those of human therapeutic levels. The acute protocol provided a full dose response in 1 week. The chronic administration protocol further differentiated drugs that may be effective long term. The gastric tube facilitates a less stressful, humane, and consistent administration of multiple doses.

Addressing the problems of treatment failure in epilepsy: You cannot fix what you do not understand

“…At least two studies have shown that with repeat dosing, levetiracetam rapidly loses its efficacy, even with high doses. 30,31 There are also studies that demonstrate that with longer term dosing, a pattern of incomplete response can be seen over several weeks of chronic treatment. Using existing models over the longer term may allow researchers to develop new insights into the effects of drugs on epilepsy and to analyze the timedependent or chronic aspects of how epilepsy medications lose their efficacy or cause toxicity.…”