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

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Abstract

Control of epilepsy has primarily focused on suppressing seizure activity by antiepileptic drugs (AEDs) after epilepsy has developed. AEDs have greatly improved the lives of people with epilepsy. However, the belief that AEDs, in addition to suppressing seizures, alter the underlying epileptogenic process and, in doing so, the course of the disease and its prognosis, is not supported by the current clinical and experimental data. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. A number of AEDs have been evaluated in clinical trials to test whether they prevent epileptogenesis in humans, but to date no drug has been shown to be effective in such trials. Thus, there is a pressing need for drugs that are truly antiepileptogenic to either prevent epilepsy or alter its natural course. For this purpose, animal models of epilepsy are an important prerequisite. There are various animal models with chronic brain dysfunctions thought to reflect the processes underlying human epilepsy. Such chronic models of epilepsy include the kindling model of temporal lobe epilepsy (TLE), post-status models of TLE in which epilepsy develops after a sustained status epilepticus, and genetic models of different types of epilepsy. Currently, the kindling model and post-status models, such as the pilocarpine or kainate models, are the most widely used models for studies on epileptogenic processes and on drug targets by which epilepsy can be prevented or modified. Furthermore, the seizures in these models can be used for testing of antiepileptic drug effects. A comparison of the pharmacology of chronic models with models of acute (reactive or provoked) seizures in previously healthy (non-epileptic) animals, such as the maximal electroshock seizure test, demonstrates that drug testing in chronic models of epilepsy yields data which are more predictive of clinical efficacy and adverse effects, so that chronic models should be used relatively early in drug development to minimize false positives. Interestingly, the pharmacology of elicited kindled seizures in fully kindled rats and spontaneous recurrent seizures in post-status models is remarkably similar. However, when these models are used for studying the antiepileptogenic effects of drugs, marked differences between models exist, indicating that the processes underlying epileptogenesis differ among models, even among different post-status models of TLE. A problem for clinical validation of TLE models is the lack of an AED, which effectively prevents epilepsy in humans. Thus, at present, it is not possible to judge which chronic model is best suited for developing new strategies in the search for antiepileptogenic and disease-modifying drugs, but rather a battery of models should be used to avoid false negative or positive predictions.

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).

References (77)

  • B.M. Longo et al.

    Supragranular mossy fiber sprouting is not necessary for spontaneous seizures in the intrahippocampal kainate model of epilepsy in the rat

    Epilepsy Res.

    (1998)
  • W. Löscher

    Animal models of intractable epilepsy

    Prog. Neurobiol.

    (1997)
  • W. Löscher

    Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy

    Prog. Neurobiol.

    (1998)
  • W. Löscher

    New visions in the pharmacology of anticonvulsion

    Eur. J. Pharmacol.

    (1998)
  • W. Löscher et al.

    Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations

    Epilepsy Res.

    (1988)
  • W. Löscher et al.

    Responses to NMDA receptor antagonists altered by epileptogenesis

    Trends Pharmacol. Sci.

    (1991)
  • W. Löscher et al.

    Strategies in antiepileptic drug development: is rational drug design superior to random screening and structural variation

    Epilepsy Res.

    (1994)
  • W. Löscher et al.

    Is amygdala kindling in rats a model for drug-resistant partial epilepsy

    Exp. Neurol.

    (1986)
  • W. Löscher et al.

    Does prolonged implantation of depth electrodes predispose the brain to kindling

    Brain Res.

    (1995)
  • W. Löscher et al.

    Kindling alters the anticonvulsant efficacy of phenytoin in Wistar rats

    Epilepsy Res.

    (2000)
  • M. Niebauer et al.

    Topiramate reduces neuronal injury after experimental status epilepticus

    Brain Res.

    (1999)
  • I. Niespodziany et al.

    Chronic electrode implantation entails epileptiform field potentials in rat hippocampal slices, similarly to amygdala kindling

    Epilepsy Res.

    (1999)
  • J.P. Pinel

    Effects of diazepam and diphenylhydantoin on elicited and spontaneous seizures in kindled rats: a double dissociation

    Pharmacol. Biochem. Behav.

    (1983)
  • A. Pitkänen et al.

    Effects of vigabatrin treatment on status epilepticus- induced neuronal damage and mossy fiber sprouting in the rat hippocampus

    Epilepsy Res.

    (1999)
  • M. Sato et al.

    Kindling: basic mechanisms and clinical validity

    Electroenceph. Clin. Neurophysiol.

    (1990)
  • J. Tuunanen et al.

    Do seizures cause neuronal damage in rat amygdala kindling

    Epilepsy Res.

    (2000)
  • M.E. Barton et al.

    Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy

    Epilepsy Res.

    (2002)
  • C.W. Bazil et al.

    Advances in the medical treatment of epilepsy

    Annu. Rev. Med.

    (1998)
  • A.R. Bolanos et al.

    Comparison of valproate and phenobarbital treatment after status epilepticus in rats

    Neurology

    (1998)
  • Brandt, C., Glien, M. Löscher, W., 2002. Overkindling-induced neurodegeneration in the hilus is not associated with the...
  • W.C. Brown et al.

    Comparative assay of antiepileptic drugs by ‘pychomotor’ seizure test and minimal electroshock threshold test

    J. Pharmacol. Exp. Ther.

    (1953)
  • T.R. Browne et al.

    Epilepsy New Engl. J. Med.

    (2001)
  • A.J. Cole

    Is epilepsy a progressive disease? The neurobiological consequences of epilepsy

    Epilepsia

    (2000)
  • Ebert, U., Brandt, C., Löscher, W., 2002. Delayed sclerosis, neuroprotection and limbic epileptogenesis after status...
  • Engel, J.J., 1996. Clinical evidence for the progressive nature of epilepsy. Epilepsy Res. (Suppl. 12)...
  • Glien, M., Brandt, C., Potschka, H., Löscher, W., 2002. Effects of the novel antiepileptic drug levetiracetam on...
  • J.H. Goodman

    Experimental models of status epilepticus

  • J.A. Gorter et al.

    Progression of spontaneous seizures after status epilepticus is associated with mossy fibre sprouting and extensive bilateral loss of hilar parvalbumin and somatostatin-immunoreactive neurons

    Eur. J. Neurosci.

    (2001)
  • Cited by (451)

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