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Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy

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Abstract

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.

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Acknowledgements

The authors wish to thank Dr. Cameron Metcalf, University of Utah, and Dr. Shamsi Raessi, NINDS Epilepsy Therapy Screening Program, for helpful discussions and data retrieval. The authors also gratefully acknowledge the assistance of Dr. John Kehne and Dr. Brian Klein, NINDS Epilepsy Therapy Screening Program, for helpful discussions and invaluable review of initial drafts of this manuscript. This work was supported by the National Institute of Neurological Disorder and Stroke’s Epilepsy Therapy Screening Program contract HHSN 271201100029 C to H. Steve White. In December 2015, the contract HHSN 271201100029 C was transferred to KSW. Lastly, the authors acknowledge the intellectual and scientific contributions of Dr. H. Steve White to the conception and implementation of the initial phases of this revised testing flow chart. While not listed as an author, this work would not have been completed without Dr. White’s input and scientific guidance developed through numerous years of experience with the NINDS Epilepsy Therapy Screening Program. This manuscript is submitted as a contribution to a special issue of Neurochemical Research in honor of Dr. White’s career.

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Authors and Affiliations

  1. Department of Pharmacy, University of Washington, Seattle, WA, 98195, USA

    Melissa L. Barker-Haliski

  2. Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA

    Kristina Johnson, Peggy Billingsley, Jennifer Huff, Laura J. Handy, Rizvana Khaleel, Zhenmei Lu, Matthew J. Mau, Timothy H. Pruess, Carlos Rueda, Gerald Saunders, Tristan K. Underwood, Fabiola Vanegas, Misty D. Smith, Peter J. West & Karen S. Wilcox

  3. Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, UT, 84112, USA

    Misty D. Smith, Peter J. West & Karen S. Wilcox

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  1. Melissa L. Barker-Haliski
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  2. Kristina Johnson
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  3. Peggy Billingsley
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  4. Jennifer Huff
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  6. Rizvana Khaleel
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  7. Zhenmei Lu
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  15. Peter J. West
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  16. Karen S. Wilcox
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Correspondence to Melissa L. Barker-Haliski.

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Barker-Haliski, M.L., Johnson, K., Billingsley, P. et al. Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy. Neurochem Res 42, 1904–1918 (2017). https://doi.org/10.1007/s11064-017-2227-7

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