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Neurochemical Research

, Volume 42, Issue 7, pp 1926–1938 | Cite as

The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?

  • Wolfgang LöscherEmail author
Original Paper

Abstract

Epilepsy, a prevalent neurological disease characterized by spontaneous recurrent seizures (SRS), is often refractory to treatment with anti-seizure drugs (ASDs), so that more effective ASDs are urgently needed. For this purpose, it would be important to develop, validate, and implement new animal models of pharmacoresistant epilepsy into drug discovery. Several chronic animal models with difficult-to-treat SRS do exist; however, most of these models are not suited for drug screening, because drug testing on SRS necessitates laborious video-EEG seizure monitoring. More recently, it was proposed that, instead of monitoring SRS, chemical or electrical induction of acute seizures in epileptic rodents may be used as a surrogate for testing the efficacy of novel ASDs against refractory SRS. Indeed, several ASDs were shown to lose their efficacy on acute seizures, when such seizures were induced by pentylenetetrazole (PTZ) in epileptic rather than nonepileptic rats, whereas this was not observed when using the maximal electroshock seizure test. Subsequent studies confirmed the loss of anti-seizure efficacy of valproate against PTZ-induced seizures in epileptic mice, but several other ASDs were more potent against PTZ in epileptic than nonepileptic mice. This was also observed when using the 6-Hz model of partial seizures in epileptic mice, in which the potency of levetiracetam, in particular, was markedly increased compared to nonepileptic animals. Overall, these observations suggest that performing acute seizure tests in epileptic rodents provides valuable information on the pharmacological profile of ASDs, in particular those with mechanisms inherent to disease-induced brain alterations. However, it appears that further work is needed to define optimal approaches for acute seizure induction and generation of epileptic/drug refractory animals that would permit reliable screening of new ASDs with improved potential to provide seizure control in patients with pharmacoresistant epilepsy.

Keywords

Antiepileptic drugs Anti-seizure drugs Pentylenetetrazole Maximal electroshock seizure test 6-Hz seizure model Kindling 

Abbreviations

AED

Antiepileptic drug

ASD

Anti-seizure drug

ASP

Anticonvulsant Screening Program

BUM5

N,N-dimethylaminoethylester of bumetanide

CC

Convulsant current

ED50

Median effective dose

EEG

Electroencephalogram

ETSP

Epilepsy Therapy Screening Program

GAERS

Genetic absence epilepsy rats from strasbourg

GEPR

Genetically epilepsy-prone rat

MES

Maximal electroshock seizure

MEST

MES threshold

NINDS

National Institute of Neurological Disorders and Stroke

NKCC

N-K-2Cl cotransporter

PTZ

Pentylenetetrazole

SE

Status epilepticus

SRS

Spontaneous recurrent seizures

SV2A

Synaptic vesicle protein 2A

TLE

Temporal lobe epilepsy

Notes

Acknowledgments

The author thanks Michael A. Rogawski, Henrik Klitgaard, Graeme Sills, Stanislaw Jerzy Czuczwar, Luiz E. Mello, Kathrin Töllner, Claudia Brandt, Marion Bankstahl, and Manuela Gernert for excellent comments on previous versions of the manuscript and Kathrin Töllner for contributing unpublished data from PTZ seizure threshold experiments in epileptic and naive mice. The author’s own studies were supported by grants from the Deutsche Forschungsgemeinschaft (Bonn, Germany) and funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement no 602102 (EPITARGET).

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Pharmacology, Toxicology and PharmacyCenter for Systems Neuroscience, University of Veterinary MedicineHannoverGermany

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