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Use of epileptic animals for adverse effect testing
Henrik Klitgaard1, Alain Matagne, Yves Lamberty
1Preclinical CNS Research, UCB S.A. Pharma Sector, Chemin du Foriest, Braine-l'Alleud, Belgium. henrik.klitgaard@ucb-group.com
Epilepsy Research
|August 2, 2002
Summary
Predicting antiepileptic drug (AED) side effects requires testing in epileptic models, not just healthy ones. Limbic kindling in rodents reveals heightened susceptibility to adverse effects, crucial for clinical utility assessments.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Assessing antiepileptic drug (AED) clinical utility relies on the therapeutic index, balancing efficacy and adverse effects.
- Preclinical adverse effect quantification typically uses healthy rodents, but this model's validity for epilepsy patients is uncertain.
- Epilepsy involves brain dysfunction that may interact with drug effects, complicating predictions from healthy models.
Purpose of the Study:
- To evaluate the validity of using healthy versus epileptic animal models for predicting adverse effects of antiepileptic drugs (AEDs).
- To determine if specific epilepsy models, like limbic kindling, are more relevant for preclinical adverse effect testing of novel AED candidates.
- To investigate the susceptibility of different epilepsy models to behavioral and cognitive alterations induced by NMDA antagonists and AEDs.
Main Methods:
- Induction of limbic kindling in rodents (mice and rats) via corneal or amygdala stimulation.
- Administration of NMDA antagonists and established AEDs to kindled and control animals.
- Assessment of behavioral and cognitive alterations in response to drug administration.
- Comparison of susceptibility in limbic kindled animals versus animals with chemically induced seizures or inborn epilepsy.
Main Results:
- Limbic kindling induced permanent susceptibility to behavioral and cognitive alterations from NMDA antagonists and certain AEDs, unlike chemical kindling.
- Inborn epilepsy models (audiogenic, photosensitive) did not show enhanced susceptibility to NMDA antagonists.
- Genetic absence epilepsy rats exhibited severe adverse effects and motor function deterioration with AEDs, more so than normal animals.
Conclusions:
- Epileptic animal models, particularly those with limbic kindling, are more relevant for preclinical adverse effect testing of AEDs than healthy models.
- The epileptic condition itself can influence drug responses, necessitating the inclusion of epileptic subjects in safety evaluations.
- Limbic kindling represents a sensitive and relevant preclinical approach for assessing the adverse effect profiles of new AED candidates.