How do we choose the appropriate animal model for antiseizure therapy development?

Abstract

Introduction: Epilepsy affects over 65 million people worldwide, and despite the numerous therapies that are currently available for the symptomatic management of chronic seizures, a substantial proportion of the population has not achieved adequate seizure control. Developing more effective and better-tolerated therapies will benefit patients worldwide. Areas covered: This article will discuss the relevant preclinical models that have been instrumental to the development of over 20 antiseizure drugs (ASDs) currently on the market today. While there have been meaningful therapies already developed over the last several decades, this article will highlight remaining areas of unmet medical need. Innovative models of pharmacoresistant epilepsy may advance therapies for patients who currently do not attain sufficient seizure control in the absence of adverse effects. There also remains a need to identify improved therapies for special patient populations, including the very young and old. Expert opinion: ASD development will still find utility in the established models that have been instrumental to the identification of impactful therapies. However, there should now be greater emphasis to implement those models in young and aged rodents to advance novel therapies for patients who are still in need of better tolerated or more effective therapies, such as pediatric and elderly patients.

Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype

“…The CKM is a well established animal model of temporal lobe epilepsy frequently used for ASD discovery (Barker-Haliski et al, 2017a;Kehne et al, 2017). Further, this model demonstrates a pharmacological profile that is consistent with the clinically validated amygdala-kindled rat model that identified levetiracetam (Matagne and Klitgaard, 1998;Barker-Haliski, 2019). CNS inflammation is also observed in CKM (Loewen et al, 2016).…”

Alzheimer’s Disease and Epilepsy: A Perspective on the Opportunities for Overlapping Therapeutic Innovation

“…2 a), but basic science has not sufficiently responded to address this clinical need. ASD discovery is not traditionally conducted in aged rodents [ 25 – 28 ]. Just as the use of juvenile Scn1a ± mice has uncovered novel treatments for Dravet syndrome (e.g., cannabidiol [ 29 ]), a rare pediatric epileptic encephalopathy, there is substantial opportunity to more frequently integrate aged animals, and in particular aged AD models, into ASD discovery to advance novel treatments and identify novel therapeutic targets (Fig.…”

Reductions in Hydrogen Sulfide Precede Onset of Mitochondrial Quality Control in the Corneal Kindled Mouse Model of Epilepsy

“…Our study is the first to demonstrate rapid reductions in plasma H2S levels following a single seizure. The mouse MES test is a well-characterized model of generalized tonicclonic seizure and is routinely implemented for drug discovery [36,41]. The MES model is substantially differentiated from the pharmacoresistant 6 Hz 44 mA seizure model in its engagement of hippocampal and limbic structures [42], as well as a differentiated pharmacological sensitivity [42][43][44][45][46][47].…”