title: Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy.
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.
authors.affiliation: Department of Pharmacy, University of Washington, Seattle, WA, 98195, USA. mhaliski@uw.edu.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Barker-Haliski
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Peggy
authors.initials: P
authors.lastname: Billingsley
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huff
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Handy
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Rizvana
authors.initials: R
authors.lastname: Khaleel
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Zhenmei
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Mau
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pruess
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rueda
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Saunders
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Tristan K
authors.initials: TK
authors.lastname: Underwood
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Vanegas
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.|Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Misty D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.|Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: West
authors.affiliation: Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT, 84112, USA.|Department of Pharmacology & Toxicology, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Wilcox
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards*; D000069279:Drug Resistant Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D004597:Electroshock / Q000009:adverse effects; D007608:Kainic Acid / Q000633:toxicity; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D007608:Kainic Acid
keywords: 6 Hz test; Animal models; Antiseizure drugs; Corneal kindling; M-CPP; N6-cyclopentyladenosine; Valproic acid