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Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs

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Abstract

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

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Abbreviations

ADD:

Antiepileptic drug development

ASD:

Antiseizure drugs

ASP:

Anticonvulsant Screening Project

CNS:

Central nervous system

ECB:

External Consultant Board

EST:

Electroshock threshold

ETSP:

Epilepsy Therapy Screening Program

GAERS:

Genetic Absence Epilepsy Rat from Strasbourg

MES:

Maximal electroshock seizure

NIH:

National Institutes of Health

NINDS:

National Institutes of Neurological Disorders and Stroke

NMDA:

N-methyl-d-aspartate

PANAChE:

Public access to neuroactive and anticonvulsant chemical evaluations

P-gp:

P-glycoprotein

PTZ:

Pentylenetetrazole

s.c.:

Subcutaneous

SRS:

Spontaneous recurrent seizures

TBI:

Traumatic brain injury

TLE:

Temporal lobe epilepsy

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Acknowledgements

I thank my colleagues and friends Harvey Kupferberg and Steve White for critically reading a first version of this review and John Kehne for providing Fig. 4. WL is a member of the External Consultant Board (ECB) of the ETSP and thanks the other ECB members and all colleagues from the NINDS Epilepsy Branch and ETSP contract site in Utah for fruitful discussions on how to improve ASD discovery. The author’s own studies have been supported by grants from the German Research Foundation (DFG, Bonn, Germany; Grant # LO 274/1 - LO 274/16), the National Institutes of Health (NIH; Bethesda, MD, USA: Grant # R21 NS049592-01), the European Union’s Seventh Framework Programme (FP7) under grant agreements 201380 (EURIPIDES) and 602102 (EPITARGET), and the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony in Germany.

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  1. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Bünteweg 17, 30559, Hanover, Germany

    Wolfgang Löscher

  2. Center for Systems Neuroscience, Hanover, Germany

    Wolfgang Löscher

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  1. Wolfgang Löscher
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Correspondence to Wolfgang Löscher.

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This review is dedicated to my colleague and friend Dr. H. Steve White to acknowledge his outstanding contributions in anti-seizure drug discovery and development of novel models of drug-resistant seizures.

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Löscher, W. Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs. Neurochem Res 42, 1873–1888 (2017). https://doi.org/10.1007/s11064-017-2222-z

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  • DOI: https://doi.org/10.1007/s11064-017-2222-z

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