Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy
Introduction
Epilepsy is the most common neurological disorder after stroke, with a 0.5% prevalence, and a 2–3% life time risk of being given a diagnosis of epilepsy (Browne and Holmes, 2001). Over the last decades, there has been considerable progress in the pharmacotherapy of epilepsy, including the introduction of several new antiepileptic drugs (AEDs) and improved formulations of older drugs (Bazil and Pedley, 1998, McCabe, 2000). However, despite this progress, about one third of patients with epilepsy are resistant to current pharmacotherapies (Löscher, 2002a). In patients in whom pharmacotherapy is efficacious, current AEDs do not seem to affect the progression or underlying natural history of epilepsy (Shinnar and Berg, 1996, Löscher, 2002a). Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma (Temkin, 2001, Temkin et al., 2001). Thus, there are at least three important goals for the future (Löscher, 2002a, Löscher and Schmidt, 2002): (1) Better understanding of basic mechanisms of the processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (2) improved understanding of biological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of resistance; and (3) development of disease-modifying therapies, inhibiting the progression of epilepsy. To achieve these goals, animal models of epilepsy are the most important prerequisite.
Apart from the bromides and phenobarbital, the anticonvulsant effect of all old and new AEDs was first determined in animal models, such as the maximal electroshock seizure (MES) or the pentylenetetrazole (PTZ) seizure tests in mice or rats, demonstrating that clinical activity can be predicted by such simple laboratory models (Löscher and Schmidt, 1988, Löscher and Schmidt, 1994). However, the fact that preclinical models used for identification and development of novel AEDs have been originally validated by ‘old’ AEDs may explain that none of the new AEDs possess significant advantages in antiepileptic efficacy towards the old drugs, so that the problem of intractable or difficult-to-control seizures has not been changed to any significant extent by the development of new AEDs (Löscher, 2002a). Furthermore, because the MES and PTZ tests are models of acute (reactive or provoked) seizures rather than models of epilepsy, it is not astonishing that none of the available AEDs which were discovered by these tests seems to be capable of preventing or modifying epilepsy (Löscher, 2002a). Thus, models simulating the chronic brain dysfunctions leading to epilepsy should be used in the search for new, more efficacious drugs. Such chronic models of epilepsy are available, but, except the kindling model, have not been used to any extent in drug development thus far. In the present review, results from drug testing in kindling and different models with recurrent spontaneous seizures will be described and discussed. Furthermore, I will also compare the pharmacology of AEDs in acute versus chronic models to demonstrate how the brain dysfunctions induced by epilepsy change the efficacy and toxicity of these drugs. In the following, the term ‘acute’ (reactive or provoked) is meant for models in which a seizure is induced by electrical or chemical stimulation in naive, healthy (non-epileptic) animals, while the term ‘chronic’ means models that use animals, which have been made epileptic by electrical or chemical means or that use animals with inborn epilepsy. The terms ‘anticonvulsant’ and ‘antiepileptic’ are used synonymously to mean ‘anti-seizure’ (anti-ictal’) drug effects, while the term ‘antiepileptogenic’ is used to indicate preventing or altering epilepsy.
Section snippets
Overview of chronic models of epilepsy
There are innumerable animal models of epilepsy or epileptic seizures (Löscher, 1999), but only few chronic models of epilepsy are currently used for pharmacological studies of epilepsy or epileptic seizures (Table 1). Chronic models of epilepsy can be divided into models of acquired (symptomatic) epilepsy and models of genetic (idiopathic) epilepsy. The first category includes models, in which epilepsy or epilepsy-like conditions are induced by electrical or chemical methods in previously
Pharmacology of seizures in acute vs. chronic models
The MES test is the most widely used animal model in AED discovery, because seizure induction is simple and the predictive value for detecting clinically effective AEDs is high (White et al., 1995, Löscher, 1999, White, 2002). The MES test identifies agents with activity against generalized tonic–clonic seizures (White et al., 1995, White, 1997). Using clinically established AEDs, the pharmacology of acute MES does not differ from the pharmacology of generalized tonic–clonic seizures in genetic
Pharmacology of elicited versus spontaneous seizures in chronic models
Data of Pinel (1983) have indicated that the pharmacology of elicited seizures may differ from the pharmacology of spontaneous seizures even in the same model. Thus, in fully kindled rats, diazepam was more effective than phenytoin in suppressing motor seizures elicited by amygdala stimulation (Pinel, 1983). However, when the kindled rats were further stimulated until the occurrence of spontaneous seizures, the effect of these drugs on the incidence of spontaneous seizures was just the opposite
Use of chronic models for studies on pharmacological prevention of epilepsy
Known potential causes of epilepsy account for at least one third of epilepsies and include brain tumors, CNS infections, traumatic brain injury, developmental malformations, perinatal insults, cerebrovascular disease, febrile seizures, and status epilepticus (Annegers et al., 1996). For instance, 10% of all acquired epilepsies develop after status epilepticus, and the risk of developing epilepsy as a sequela to status epilepticus ranges between 30 and 80% (Maytal et al., 1989, Hauser et al.,
Use of chronic models in the search of disease-modifying drugs
The debate continues about whether epilepsy is a progressive disease (Reynolds, 1995, Engel, 1996, Shinnar and Berg, 1996, Cole, 2000, Löscher and Leppik, 2002). Studies on progression of epilepsy in humans are restricted, because of early and chronic treatment with AEDs. Furthermore, in asking whether epilepsy is a progressive disease, the answer varies depending on which type of epilepsy is being considered. For instance, most of the primary (idiopathic) epileptic disorders, such as the
Conclusions
In epilepsy research, animal models serve a variety of purposes (White, 1997, Löscher, 1999, Kupferberg, 2001, Löscher, 2002a, White, 2002). Chronic models of epilepsy are increasingly used to study the processes leading from an initial insult to the brain, such as a status epilepticus, to spontaneous seizures (Löscher, 2002a). The aim of such studies is to enhance our understanding of the processes leading to epilepsy and to identify drug targets for antiepileptogenesis (Löscher, 2002a).
Uncited references
Halonen et al., 1996.
Acknowledgements
I wish to thank Dr H. Steve White (Anticonvulsant Screening Project, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA) and Prof. Dieter Schmidt (Epilepsy Research Group, Berlin, Germany) for discussions and constructive criticisms during the preparation of this manuscript. Our epilepsy research program is supported by grants from the Deutsche Forschungsgemeinschaft (Bonn, Germany).
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