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Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model.
Epilepsia Open 2019; 4(3):452-463EO

Abstract

Objective

The lamotrigine-resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported.

Methods

Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (~3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine-resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score < 3 in the absence of overt compound-induced side effects. Various ASDs, comprising several mechanistic classes, were administered to fully kindled, lamotrigine-resistant rats. Where possible, multiple doses of each drug were administered in order to obtain median effective dose (ED50) values.

Results

Five sodium channel blockers tested (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well-tolerated in this model. In contrast, compounds targeting either GABA receptors (clobazam, clonazepam, phenobarbital) or GABA-uptake proteins (tiagabine) produced dose-dependent efficacy against convulsive seizures. Compounds acting to modulate Ca2+ channels show differential activity: Ethosuximide was not effective, whereas gabapentin was moderately efficacious. Ezogabine and valproate were also highly effective, whereas topiramate and levetiracetam were not effective at the doses tested.

Significance

These results strengthen the conclusion that the lamotrigine-resistant amygdala kindling model demonstrates pharmacoresistance to certain ASDs, including, but not limited to, sodium channel blockers, and supports the utility of the model for helping to identify compounds with potential efficacy against pharmacoresistant seizures.

Authors+Show Affiliations

Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology University of Utah Salt Lake City UT USA.Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology University of Utah Salt Lake City UT USA.Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology University of Utah Salt Lake City UT USA.Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology University of Utah Salt Lake City UT USA.Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology University of Utah Salt Lake City UT USA.Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology University of Utah Salt Lake City UT USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31440726

Citation

Metcalf, Cameron S., et al. "Evaluation of Antiseizure Drug Efficacy and Tolerability in the Rat Lamotrigine-resistant Amygdala Kindling Model." Epilepsia Open, vol. 4, no. 3, 2019, pp. 452-463.
Metcalf CS, Huff J, Thomson KE, et al. Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. Epilepsia Open. 2019;4(3):452-463.
Metcalf, C. S., Huff, J., Thomson, K. E., Johnson, K., Edwards, S. F., & Wilcox, K. S. (2019). Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. Epilepsia Open, 4(3), pp. 452-463. doi:10.1002/epi4.12354.
Metcalf CS, et al. Evaluation of Antiseizure Drug Efficacy and Tolerability in the Rat Lamotrigine-resistant Amygdala Kindling Model. Epilepsia Open. 2019;4(3):452-463. PubMed PMID: 31440726.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. AU - Metcalf,Cameron S, AU - Huff,Jennifer, AU - Thomson,Kyle E, AU - Johnson,Kristina, AU - Edwards,Sharon F, AU - Wilcox,Karen S, Y1 - 2019/08/12/ PY - 2019/01/27/received PY - 2019/07/09/revised PY - 2019/07/21/accepted PY - 2019/8/24/entrez PY - 2019/8/24/pubmed PY - 2019/8/24/medline KW - animal models KW - antiseizure drugs KW - kindling KW - pharmacoresistant epilepsy SP - 452 EP - 463 JF - Epilepsia open JO - Epilepsia Open VL - 4 IS - 3 N2 - Objective: The lamotrigine-resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported. Methods: Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (~3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine-resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score < 3 in the absence of overt compound-induced side effects. Various ASDs, comprising several mechanistic classes, were administered to fully kindled, lamotrigine-resistant rats. Where possible, multiple doses of each drug were administered in order to obtain median effective dose (ED50) values. Results: Five sodium channel blockers tested (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well-tolerated in this model. In contrast, compounds targeting either GABA receptors (clobazam, clonazepam, phenobarbital) or GABA-uptake proteins (tiagabine) produced dose-dependent efficacy against convulsive seizures. Compounds acting to modulate Ca2+ channels show differential activity: Ethosuximide was not effective, whereas gabapentin was moderately efficacious. Ezogabine and valproate were also highly effective, whereas topiramate and levetiracetam were not effective at the doses tested. Significance: These results strengthen the conclusion that the lamotrigine-resistant amygdala kindling model demonstrates pharmacoresistance to certain ASDs, including, but not limited to, sodium channel blockers, and supports the utility of the model for helping to identify compounds with potential efficacy against pharmacoresistant seizures. SN - 2470-9239 UR - https://www.unboundmedicine.com/medline/citation/31440726/Evaluation_of_antiseizure_drug_efficacy_and_tolerability_in_the_rat_lamotrigine-resistant_amygdala_kindling_model DB - PRIME DP - Unbound Medicine ER -