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

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.

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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

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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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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. The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?. Neurochem Res 42, 1926–1938 (2017). https://doi.org/10.1007/s11064-016-2025-7

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Keywords

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